|
1
|
Murray JE, Valli E, Milazzo G, Mayoh C, Gifford AJ, Fletcher JI, Xue C, Jayatilleke N, Salehzadeh F, Gamble LD, Rouaen JRC, Carter DR, Forgham H, Sekyere EO, Keating J, Eden G, Allan S, Alfred S, Kusuma FK, Clark A, Webber H, Russell AJ, de Weck A, Kile BT, Santulli M, De Rosa P, Fleuren EDG, Gao W, Wilkinson-White L, Low JKK, Mackay JP, Marshall GM, Hilton DJ, Giorgi FM, Koster J, Perini G, Haber M, Norris MD. The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis. Nat Commun 2024; 15:5585. [PMID: 38992040 PMCID: PMC11239676 DOI: 10.1038/s41467-024-49871-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/23/2024] [Indexed: 07/13/2024] Open
Abstract
MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.
Collapse
Affiliation(s)
- Jayne E Murray
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Emanuele Valli
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Giorgio Milazzo
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Chelsea Mayoh
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Andrew J Gifford
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
- Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Randwick, NSW, Australia
| | - Jamie I Fletcher
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Chengyuan Xue
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Nisitha Jayatilleke
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Firoozeh Salehzadeh
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Laura D Gamble
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Jourdin R C Rouaen
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Daniel R Carter
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
- School of Biomedical Engineering, University of Technology Sydney, Broadway, NSW, Australia
| | - Helen Forgham
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Eric O Sekyere
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Joanna Keating
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Georgina Eden
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Sophie Allan
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Stephanie Alfred
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Frances K Kusuma
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Ashleigh Clark
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Hannah Webber
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Amanda J Russell
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Antoine de Weck
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Benjamin T Kile
- Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Martina Santulli
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Piergiuseppe De Rosa
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Emmy D G Fleuren
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Weiman Gao
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
| | - Lorna Wilkinson-White
- Sydney Analytical Core Research Facility, The University of Sydney, Sydney, NSW, Australia
| | - Jason K K Low
- School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
| | - Joel P Mackay
- School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
| | - Glenn M Marshall
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Douglas J Hilton
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Federico M Giorgi
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Jan Koster
- Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Giovanni Perini
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Michelle Haber
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Murray D Norris
- Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.
| |
Collapse
|
|
2
|
Veschi V, Durinck K, Thiele CJ, Speleman F. Neuroblastoma Epigenetic Landscape: Drugging Opportunities. PEDIATRIC ONCOLOGY 2024:71-95. [DOI: 10.1007/978-3-031-51292-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
3
|
Valenti GE, Roveri A, Venerando R, Menichini P, Monti P, Tasso B, Traverso N, Domenicotti C, Marengo B. PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis. Antioxidants (Basel) 2023; 13:3. [PMID: 38275623 PMCID: PMC10812464 DOI: 10.3390/antiox13010003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 01/27/2024] Open
Abstract
Neuroblastoma (NB) is a paediatric cancer with noteworthy heterogeneity ranging from spontaneous regression to high-risk forms that are characterised by cancer relapse and the acquisition of drug resistance. The most-used anticancer drugs exert their cytotoxic effect by inducing oxidative stress, and long-term therapy has been demonstrated to cause chemoresistance by enhancing the antioxidant response of NB cells. Taking advantage of an in vitro model of multidrug-resistant (MDR) NB cells, characterised by high levels of glutathione (GSH), the overexpression of the oncoprotein BMI-1, and the presence of a mutant P53 protein, we investigated a new potential strategy to fight chemoresistance. Our results show that PTC596, an inhibitor of BMI-1, exerted a high cytotoxic effect on MDR NB cells, while PRIMA-1MET, a compound able to reactivate mutant P53, had no effect on the viability of MDR cells. Furthermore, both PTC596 and PRIMA-1MET markedly reduced the expression of epithelial-mesenchymal transition proteins and limited the clonogenic potential and the cancer stemness of MDR cells. Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1MET and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering ferroptosis, could be a promising approach to fight chemoresistance.
Collapse
Affiliation(s)
- Giulia Elda Valenti
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
| | - Antonella Roveri
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy; (A.R.); (R.V.)
| | - Rina Venerando
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy; (A.R.); (R.V.)
| | - Paola Menichini
- Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.M.); (P.M.)
| | - Paola Monti
- Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.M.); (P.M.)
| | - Bruno Tasso
- Department of Pharmacy, University of Genoa, 16148 Genoa, Italy;
| | - Nicola Traverso
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
| | - Cinzia Domenicotti
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
| | - Barbara Marengo
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
| |
Collapse
|
|
4
|
Zhai L, Balachandran A, Larkin R, Seneviratne JA, Chung SA, Lalwani A, Tsubota S, Beck D, Kadomatsu K, Beckers A, Durink K, De Preter K, Speleman F, Haber M, Norris MD, Swarbrick A, Cheung BB, Marshall GM, Carter DR. Mitotic Dysregulation at Tumor Initiation Creates a Therapeutic Vulnerability to Combination Anti-Mitotic and Pro-Apoptotic Agents for MYCN-Driven Neuroblastoma. Int J Mol Sci 2023; 24:15571. [PMID: 37958555 PMCID: PMC10649872 DOI: 10.3390/ijms242115571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023] Open
Abstract
MYCN amplification occurs in approximately 20-30% of neuroblastoma patients and correlates with poor prognosis. The TH-MYCN transgenic mouse model mimics the development of human high-risk neuroblastoma and provides strong evidence for the oncogenic function of MYCN. In this study, we identified mitotic dysregulation as a hallmark of tumor initiation in the pre-cancerous ganglia from TH-MYCN mice that persists through tumor progression. Single-cell quantitative-PCR of coeliac ganglia from 10-day-old TH-MYCN mice revealed overexpression of mitotic genes in a subpopulation of premalignant neuroblasts at a level similar to single cells derived from established tumors. Prophylactic treatment using antimitotic agents barasertib and vincristine significantly delayed the onset of tumor formation, reduced pre-malignant neuroblast hyperplasia, and prolonged survival in TH-MYCN mice. Analysis of human neuroblastoma tumor cohorts showed a strong correlation between dysregulated mitosis and features of MYCN amplification, such as MYC(N) transcriptional activity, poor overall survival, and other clinical predictors of aggressive disease. To explore the therapeutic potential of targeting mitotic dysregulation, we showed that genetic and chemical inhibition of mitosis led to selective cell death in neuroblastoma cell lines with MYCN over-expression. Moreover, combination therapy with antimitotic compounds and BCL2 inhibitors exploited mitotic stress induced by antimitotics and was synergistically toxic to neuroblastoma cell lines. These results collectively suggest that mitotic dysregulation is a key component of tumorigenesis in early neuroblasts, which can be inhibited by the combination of antimitotic compounds and pro-apoptotic compounds in MYCN-driven neuroblastoma.
Collapse
Affiliation(s)
- Lei Zhai
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
| | - Anushree Balachandran
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
| | - Rebecca Larkin
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
| | - Janith A. Seneviratne
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
| | - Sylvia A. Chung
- Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2031, Australia
| | - Amit Lalwani
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
| | - Shoma Tsubota
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan
| | - Dominik Beck
- School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Kenji Kadomatsu
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan
| | - Anneleen Beckers
- Department of Biomolecular Medicine, Cancer Research Institute Ghent, Ghent University, 9000 Ghent, Belgium
| | - Kaat Durink
- Department of Biomolecular Medicine, Cancer Research Institute Ghent, Ghent University, 9000 Ghent, Belgium
| | - Katleen De Preter
- Department of Biomolecular Medicine, Cancer Research Institute Ghent, Ghent University, 9000 Ghent, Belgium
| | - Frank Speleman
- Department of Biomolecular Medicine, Cancer Research Institute Ghent, Ghent University, 9000 Ghent, Belgium
| | - Michelle Haber
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
| | - Murray D. Norris
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
- UNSW Centre for Childhood Cancer Research, University of New South Wales, Sydney, NSW 2031, Australia
| | - Alexander Swarbrick
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Belamy B. Cheung
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW 2031, Australia
| | - Glenn M. Marshall
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW 2031, Australia
- Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, Australia
| | - Daniel R. Carter
- Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW 2031, Australia
- School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW 2007, Australia
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW 2031, Australia
| |
Collapse
|
|
5
|
Akita N, Okada R, Mukae K, Sugino RP, Takenobu H, Chikaraishi K, Ochiai H, Yamaguchi Y, Ohira M, Koseki H, Kamijo T. Polycomb group protein BMI1 protects neuroblastoma cells against DNA damage-induced apoptotic cell death. Exp Cell Res 2023; 422:113412. [PMID: 36370852 DOI: 10.1016/j.yexcr.2022.113412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 10/31/2022] [Accepted: 11/05/2022] [Indexed: 11/10/2022]
Abstract
The overexpression of BMI1, a polycomb protein, correlates with cancer development and aggressiveness. We previously reported that MYCN-induced BMI1 positively regulated neuroblastoma (NB) cell proliferation via the transcriptional inhibition of tumor suppressors in NB cells. To assess the potential of BMI1 as a new target for NB therapy, we examined the effects of reductions in BMI1 on NB cells. BMI1 knockdown (KD) in NB cells significantly induced their differentiation for up to 7 days. BMI1 depletion significantly induced apoptotic NB cell death for up to 14 days along with the activation of p53, increases in p73, and induction of p53 family downstream molecules and pathways, even in p53 mutant cells. BMI1 depletion in vivo markedly suppressed NB xenograft tumor growth. BMI1 reductions activated ATM and increased γ-H2AX in NB cells. These DNA damage signals and apoptotic cell death were not canceled by the transduction of the polycomb group molecules EZH2 and RING1B. Furthermore, EZH2 and RING1B KD did not induce apoptotic NB cell death to the same extent as BMI1 KD. Collectively, these results suggest the potential of BMI1 as a target of molecular therapy for NB and confirmed, for the first time, the shared role of PcG proteins in the DNA damage response of NB cells.
Collapse
Affiliation(s)
- Nobuhiro Akita
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Japan; Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan; Department of Pediatrics, Chiba University School of Medicine, Japan; Research Institute for Clinical Oncology, Saitama Cancer Center, Japan
| | - Ryu Okada
- Research Institute for Clinical Oncology, Saitama Cancer Center, Japan; Department of Graduate School of Science and Engineering, Saitama University, Japan
| | - Kyosuke Mukae
- Research Institute for Clinical Oncology, Saitama Cancer Center, Japan
| | - Ryuichi P Sugino
- Research Institute for Clinical Oncology, Saitama Cancer Center, Japan
| | - Hisanori Takenobu
- Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan; Research Institute for Clinical Oncology, Saitama Cancer Center, Japan.
| | - Koji Chikaraishi
- Department of Pediatrics, Chiba University School of Medicine, Japan; Research Institute for Clinical Oncology, Saitama Cancer Center, Japan
| | - Hidemasa Ochiai
- Department of Pediatrics, Chiba University School of Medicine, Japan
| | - Yohko Yamaguchi
- Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan; Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Japan
| | - Miki Ohira
- Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan; Research Institute for Clinical Oncology, Saitama Cancer Center, Japan
| | - Haruhiko Koseki
- Developmental Genetics Group, RIKEN Research Center for Allergy and Immunology, Japan
| | - Takehiko Kamijo
- Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan; Research Institute for Clinical Oncology, Saitama Cancer Center, Japan; Department of Graduate School of Science and Engineering, Saitama University, Japan.
| |
Collapse
|
|
6
|
Rodriguez-Ramirez C, Zhang Z, Warner KA, Herzog AE, Mantesso A, Zhang Z, Yoon E, Wang S, Wicha MS, Nör JE. p53 Inhibits Bmi-1-driven Self-Renewal and Defines Salivary Gland Cancer Stemness. Clin Cancer Res 2022; 28:4757-4770. [PMID: 36048559 PMCID: PMC9633396 DOI: 10.1158/1078-0432.ccr-22-1357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 08/01/2022] [Accepted: 08/30/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Mucoepidermoid carcinoma (MEC) is a poorly understood salivary gland malignancy with limited therapeutic options. Cancer stem cells (CSC) are considered drivers of cancer progression by mediating tumor recurrence and metastasis. We have shown that clinically relevant small molecule inhibitors of MDM2-p53 interaction activate p53 signaling and reduce the fraction of CSC in MEC. Here we examined the functional role of p53 in the plasticity and self-renewal of MEC CSC. EXPERIMENTAL DESIGN Using gene silencing and therapeutic activation of p53, we analyzed the cell-cycle profiles and apoptosis levels of CSCs in MEC cell lines (UM-HMC-1, -3A, -3B) via flow cytometry and looked at the effects on survival/self-renewal of the CSCs through sphere assays. We evaluated the effect of p53 on tumor development (N = 51) and disease recurrence (N = 17) using in vivo subcutaneous and orthotopic murine models of MEC. Recurrence was followed for 250 days after tumor resection. RESULTS Although p53 activation does not induce MEC CSC apoptosis, it reduces stemness properties such as self-renewal by regulating Bmi-1 expression and driving CSC towards differentiation. In contrast, downregulation of p53 causes expansion of the CSC population while promoting tumor growth. Remarkably, therapeutic activation of p53 prevented CSC-mediated tumor recurrence in preclinical trials. CONCLUSIONS Collectively, these results demonstrate that p53 defines the stemness of MEC and suggest that therapeutic activation of p53 might have clinical utility in patients with salivary gland MEC.
Collapse
Affiliation(s)
| | - Zhaocheng Zhang
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Kristy A. Warner
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Alexandra E. Herzog
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Andrea Mantesso
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Zhixiong Zhang
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
| | - Eusik Yoon
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
| | - Shaomeng Wang
- Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI, USA,Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Max S. Wicha
- Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Jacques E. Nör
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA,Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA,Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, 48109, USA
| |
Collapse
|
|
7
|
Fessé P, Nyman J, Hermansson I, Book ML, Ahlgren J, Turesson I. Human cutaneous interfollicular melanocytes differentiate temporarily under genotoxic stress. iScience 2022; 25:105238. [PMID: 36274944 PMCID: PMC9579029 DOI: 10.1016/j.isci.2022.105238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 08/30/2022] [Accepted: 09/26/2022] [Indexed: 12/05/2022] Open
Abstract
DNA-damage response of cutaneous interfollicular melanocytes to fractionated radiotherapy was investigated by immunostaining of tissue sections from punch biopsies collected before, during, and after the treatment of patients for breast cancer. Our clinical assay with sterilized hair follicles, excluded the migration of immature melanocytes from the bulge, and highlighted interfollicular melanocytes as an autonomous self-renewing population. About thirty percent are immature. Surrounding keratinocytes induced and maintained melanocyte differentiation as long as treatment was ongoing. Concomitant with differentiation, melanocytes were protected from apoptosis by transient upregulation of Bcl-2 and CXCR2. CXCR2 upregulation also indicated the instigation of premature senescence, preventing proliferation. The stem cell factor BMI1 was constitutively expressed exclusively in interfollicular melanocytes and further upregulated upon irradiation. BMI1 prevents apoptosis, terminal differentiation, and premature senescence, allowing dedifferentiation post-treatment, by suppressing the p53/p21-and p16-mediated response and upregulating CXCR2 to genotoxic damage. The pre-treatment immature subset of interfollicular melanocytes was restored after the exposure ended.
Collapse
Affiliation(s)
- Per Fessé
- Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden
- Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden
| | - Jan Nyman
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ingegerd Hermansson
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maj-Lis Book
- Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden
| | - Johan Ahlgren
- Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro Sweden
| | - Ingela Turesson
- Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
8
|
Zanotti S, Decaesteker B, Vanhauwaert S, De Wilde B, De Vos WH, Speleman F. Cellular senescence in neuroblastoma. Br J Cancer 2022; 126:1529-1538. [PMID: 35197583 PMCID: PMC9130206 DOI: 10.1038/s41416-022-01755-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 01/14/2022] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma is a tumour that arises from the sympathoadrenal lineage occurring predominantly in children younger than five years. About half of the patients are diagnosed with high-risk tumours and undergo intensive multi-modal therapy. The success rate of current treatments for high-risk neuroblastoma is disappointingly low and survivors suffer from multiple therapy-related long-term side effects. Most chemotherapeutics drive cancer cells towards cell death or senescence. Senescence has long been considered to represent a terminal non-proliferative state and therefore an effective barrier against tumorigenesis. This dogma, however, has been challenged by recent observations that infer a much more dynamic and reversible nature for this process, which may have implications for the efficacy of therapy-induced senescence-oriented treatment strategies. Neuroblastoma cells in a dormant, senescent-like state may escape therapy, whilst their senescence-associated secretome may promote inflammation and invasiveness, potentially fostering relapse. Conversely, due to its distinct molecular identity, senescence may also represent an opportunity for the development of novel (combination) therapies. However, the limited knowledge on the molecular dynamics and diversity of senescence signatures demands appropriate models to study this process in detail. This review summarises the molecular knowledge about cellular senescence in neuroblastoma and investigates current and future options towards therapeutic exploration.
Collapse
Affiliation(s)
- Sofia Zanotti
- grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, 2610 Belgium ,grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.510942.bCancer Research Institute Ghent (CRIG), Ghent, 9000 Belgium
| | - Bieke Decaesteker
- grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.510942.bCancer Research Institute Ghent (CRIG), Ghent, 9000 Belgium
| | - Suzanne Vanhauwaert
- grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.510942.bCancer Research Institute Ghent (CRIG), Ghent, 9000 Belgium
| | - Bram De Wilde
- grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.5342.00000 0001 2069 7798Department of Internal Medicine and Pediatrics, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.410566.00000 0004 0626 3303Department of Pediatric Hematology Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, 9000 Belgium
| | - Winnok H. De Vos
- grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, 2610 Belgium
| | - Frank Speleman
- Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000, Belgium. .,Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
| |
Collapse
|
|
9
|
De Wyn J, Zimmerman MW, Weichert-Leahey N, Nunes C, Cheung BB, Abraham BJ, Beckers A, Volders PJ, Decaesteker B, Carter DR, Look AT, De Preter K, Van Loocke W, Marshall GM, Durbin AD, Speleman F, Durinck K. MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation. Cancers (Basel) 2021; 13:cancers13194783. [PMID: 34638267 PMCID: PMC8508013 DOI: 10.3390/cancers13194783] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Neuroblastoma is a pediatric tumor originating from the sympathetic nervous system responsible for 10–15% of all childhood cancer deaths. Half of all neuroblastoma patients present with high-risk disease, of which nearly 50% relapse and die of their disease. In addition, standard therapies cause serious lifelong side effects and increased risk for secondary tumors. Further research is crucial to better understand the molecular basis of neuroblastomas and to identify novel druggable targets. Neuroblastoma tumorigenesis has to this end been modeled in both mice and zebrafish. Here, we present a detailed dissection of the gene expression patterns that underlie tumor formation in the murine TH-MYCN-driven neuroblastoma model. We identified key factors that are putatively important for neuroblastoma tumor initiation versus tumor progression, pinpointed crucial regulators of the observed expression patterns during neuroblastoma development and scrutinized which factors could be innovative and vulnerable nodes for therapeutic intervention. Abstract Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma.
Collapse
Affiliation(s)
- Jolien De Wyn
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Mark W. Zimmerman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; (M.W.Z.); (N.W.-L.); (A.T.L.)
| | - Nina Weichert-Leahey
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; (M.W.Z.); (N.W.-L.); (A.T.L.)
| | - Carolina Nunes
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Belamy B. Cheung
- Lowy Cancer Research Centre, Children’s Cancer Institute Australia for Medical Research, UNSW Sydney, Randwick, NSW 2031, Australia; (B.B.C.); (D.R.C.); (G.M.M.)
- School of Women’s and Children’s Health, UNSW Sydney, Randwick, NSW 2031, Australia
| | - Brian J. Abraham
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA;
| | - Anneleen Beckers
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Pieter-Jan Volders
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Bieke Decaesteker
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Daniel R. Carter
- Lowy Cancer Research Centre, Children’s Cancer Institute Australia for Medical Research, UNSW Sydney, Randwick, NSW 2031, Australia; (B.B.C.); (D.R.C.); (G.M.M.)
- School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Alfred Thomas Look
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; (M.W.Z.); (N.W.-L.); (A.T.L.)
| | - Katleen De Preter
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Wouter Van Loocke
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Glenn M. Marshall
- Lowy Cancer Research Centre, Children’s Cancer Institute Australia for Medical Research, UNSW Sydney, Randwick, NSW 2031, Australia; (B.B.C.); (D.R.C.); (G.M.M.)
- Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, Australia
| | - Adam D. Durbin
- Department of Oncology, Division of Molecular Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA;
| | - Frank Speleman
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
| | - Kaat Durinck
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (J.D.W.); (C.N.); (A.B.); (P.-J.V.); (B.D.); (K.D.P.); (W.V.L.); (F.S.)
- Correspondence: ; Tel.: +32-9-332-24-51
| |
Collapse
|
|
10
|
Freire-Benéitez V, Pomella N, Millner TO, Dumas AA, Niklison-Chirou MV, Maniati E, Wang J, Rajeeve V, Cutillas P, Marino S. Elucidation of the BMI1 interactome identifies novel regulatory roles in glioblastoma. NAR Cancer 2021; 3:zcab009. [PMID: 34316702 PMCID: PMC8210184 DOI: 10.1093/narcan/zcab009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/27/2021] [Accepted: 02/28/2021] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive intrinsic brain tumour in adults. Epigenetic mechanisms controlling normal brain development are often dysregulated in GBM. Among these, BMI1, a structural component of the Polycomb Repressive Complex 1 (PRC1), which promotes the H2AK119ub catalytic activity of Ring1B, is upregulated in GBM and its tumorigenic role has been shown in vitro and in vivo. Here, we have used protein and chromatin immunoprecipitation followed by mass spectrometry (MS) analysis to elucidate the protein composition of PRC1 in GBM and transcriptional silencing of defining interactors in primary patient-derived GIC lines to assess their functional impact on GBM biology. We identify novel regulatory functions in mRNA splicing and cholesterol transport which could represent novel targetable mechanisms in GBM.
Collapse
Affiliation(s)
- Verónica Freire-Benéitez
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK
| | - Nicola Pomella
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK
| | - Thomas O Millner
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK
| | - Anaëlle A Dumas
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK
| | - Maria Victoria Niklison-Chirou
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK
| | - Eleni Maniati
- Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6AS UK
| | - Jun Wang
- Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6AS UK
| | - Vinothini Rajeeve
- Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6AS UK
| | - Pedro Cutillas
- Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6AS UK
| | - Silvia Marino
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK
| |
Collapse
|
|
11
|
Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
Collapse
Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
| |
Collapse
|
|
12
|
Chen MK, Zhou JH, Wang P, Ye YL, Liu Y, Zhou JW, Chen ZJ, Yang JK, Liao DY, Liang ZJ, Xie X, Zhou QZ, Xue KY, Guo WB, Xia M, Bao JM, Yang C, Duan HF, Wang HY, Huang ZP, Qin ZK, Liu CD. BMI1 activates P-glycoprotein via transcription repression of miR-3682-3p and enhances chemoresistance of bladder cancer cell. Aging (Albany NY) 2021; 13:18310-18330. [PMID: 34270461 PMCID: PMC8351696 DOI: 10.18632/aging.203277] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 06/04/2021] [Indexed: 12/11/2022]
Abstract
Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.
Collapse
Affiliation(s)
- Ming-Kun Chen
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Jun-Hao Zhou
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Peng Wang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Yun-Lin Ye
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China
| | - Yang Liu
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Jia-Wei Zhou
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Zi-Jian Chen
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Jian-Kun Yang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - De-Ying Liao
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Zhi-Jian Liang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Xiao Xie
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Qi-Zhao Zhou
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Kang-Yi Xue
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Wen-Bin Guo
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Ming Xia
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Ji-Ming Bao
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Cheng Yang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Hai-Feng Duan
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Hong-Yi Wang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Zhi-Peng Huang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Zi-Ke Qin
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China
| | - Cun-Dong Liu
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| |
Collapse
|
|
13
|
Tran HN, Singh HP, Guo W, Cambier L, Riggan L, Shackleford GM, Thornton ME, Grubbs BH, Erdreich-Epstein A, Qi DL, Cobrinik D. Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers. Front Oncol 2020; 10:563156. [PMID: 33425720 PMCID: PMC7793692 DOI: 10.3389/fonc.2020.563156] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 11/20/2020] [Indexed: 12/22/2022] Open
Abstract
MYC family oncoproteins MYC, MYCN, and MYCL are deregulated in diverse cancers and via diverse mechanisms. Recent studies established a novel form of MYCN regulation in MYCN-overexpressing retinoblastoma and neuroblastoma cells in which the MDM2 oncoprotein promotes MYCN translation and MYCN-dependent proliferation via a p53-independent mechanism. However, it is unclear if MDM2 also promotes expression of other MYC family members and has similar effects in other cancers. Conversely, MYCN has been shown to induce MDM2 expression in neuroblastoma cells, yet it is unclear if MYC shares this ability, if MYC family proteins upregulate MDM2 in other malignancies, and if this regulation occurs during tumorigenesis as well as in cancer cell lines. Here, we report that intrinsically high MDM2 expression is required for high-level expression of MYCN, but not for expression of MYC, in retinoblastoma, neuroblastoma, small cell lung cancer, and medulloblastoma cells. Conversely, ectopic overexpression of MYC as well as MYCN induced high-level MDM2 expression and gave rise to rapidly proliferating and MDM2-dependent cone-precursor-derived masses in a cultured retinoblastoma genesis model. These findings reveal a highly specific collaboration between the MDM2 and MYCN oncoproteins and demonstrate the origin of their oncogenic positive feedback circuit within a normal neuronal tissue.
Collapse
Affiliation(s)
- Hung N Tran
- Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Hardeep P Singh
- The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Department of Ophthalmology and Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Wenxuan Guo
- The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Program in Biomedical and Biological Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Linda Cambier
- The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Luke Riggan
- The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Gregory M Shackleford
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Matthew E Thornton
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Brendan H Grubbs
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Anat Erdreich-Epstein
- Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA, United States.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Departments of Pediatrics and Pathology, Children's Hospital Los Angeles and Keck School of Medicine, and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Dong-Lai Qi
- The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China
| | - David Cobrinik
- The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Department of Ophthalmology and Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| |
Collapse
|
|
14
|
Sarfraz M, Afzal A, Khattak S, Saddozai UAK, Li HM, Zhang QQ, Madni A, Haleem KS, Duan SF, Wu DD, Ji SP, Ji XY. Multifaceted behavior of PEST sequence enriched nuclear proteins in cancer biology and role in gene therapy. J Cell Physiol 2020; 236:1658-1676. [PMID: 32841373 DOI: 10.1002/jcp.30011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/18/2020] [Accepted: 08/04/2020] [Indexed: 01/12/2023]
Abstract
The amino acid sequence enriched with proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) is a signal-transducing agent providing unique features to its substrate nuclear proteins (PEST-NPs). The PEST motif is responsible for particular posttranslational modifications (PTMs). These PTMs impart distinct properties to PEST-NPs that are responsible for their activation/inhibition, intracellular localization, and stability/degradation. PEST-NPs participate in cancer metabolism, immunity, and protein transcription as oncogenes or as tumor suppressors. Gene-based therapeutics are getting the attention of researchers because of their cell specificity. PEST-NPs are good targets to explore as cancer therapeutics. Insights into PTMs of PEST-NPs demonstrate that these proteins not only interact with each other but also recruit other proteins to/from their active site to promote/inhibit tumors. Thus, the role of PEST-NPs in cancer biology is multivariate. It is hard to obtain therapeutic objectives with single gene therapy. An especially designed combination gene therapy might be a promising strategy in cancer treatment. This review highlights the multifaceted behavior of PEST-NPs in cancer biology. We have summarized a number of studies to address the influence of structure and PEST-mediated PTMs on activation, localization, stability, and protein-protein interactions of PEST-NPs. We also recommend researchers to adopt a pragmatic approach in gene-based cancer therapy.
Collapse
Affiliation(s)
- Muhammad Sarfraz
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China.,Faculty of Pharmacy, The University of Lahore, Lahore, Punjab, Pakistan.,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Henan University, Kaifeng, Henan, China
| | - Attia Afzal
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China.,Faculty of Pharmacy, The University of Lahore, Lahore, Punjab, Pakistan
| | - Saadullah Khattak
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China
| | - Umair A K Saddozai
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China
| | - Hui-Min Li
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China.,Department of Histology and Embryology, Cell Signal Transduction Laboratory, School of Basic Medical Sciences, Bioinformatics Centre, Institute of Biomedical Informatics, Henan University, Kaifeng, Henan, China
| | - Qian-Qian Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China
| | - Asadullah Madni
- Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Bahawalpur, Punjab, Pakistan
| | - Kashif S Haleem
- Department of Microbiology, Hazara University, Mansehra, Pakistan
| | - Shao-Feng Duan
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China.,School of Pharmacy, Institute for Innovative Drug Design and Evaluation, Henan University, Kaifeng, Henan, China
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China.,School of Stomatology, Henan University, Kaifeng, Henan, China
| | - Shao-Ping Ji
- Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Henan University, Kaifeng, Henan, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation & Kaifeng Key Laboratory of Infectious Diseases and Bio-safety, School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, China
| |
Collapse
|
|
15
|
Koifman G, Aloni-Grinstein R, Rotter V. p53 balances between tissue hierarchy and anarchy. J Mol Cell Biol 2020; 11:553-563. [PMID: 30925590 PMCID: PMC6735948 DOI: 10.1093/jmcb/mjz022] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 01/17/2019] [Accepted: 02/13/2019] [Indexed: 02/07/2023] Open
Abstract
Normal tissues are organized in a hierarchical model, whereas at the apex of these hierarchies reside stem cells (SCs) capable of self-renewal and of producing differentiated cellular progenies, leading to normal development and homeostasis. Alike, tumors are organized in a hierarchical manner, with cancer SCs residing at the apex, contributing to the development and nourishment of tumors. p53, the well-known ‘guardian of the genome’, possesses various roles in embryonic development as well as in adult SC life and serves as the ‘guardian of tissue hierarchy’. Moreover, p53 serves as a barrier for dedifferentiation and reprogramming by constraining the cells to a somatic state and preventing their conversion to SCs. On the contrary, the mutant forms of p53 that lost their tumor suppressor activity and gain oncogenic functions serve as ‘inducers of tissue anarchy’ and promote cancer development. In this review, we discuss these two sides of the p53 token that sentence a tissue either to an ordered hierarchy and life or to anarchy and death. A better understanding of these processes may open new horizons for the development of new cancer therapies.
Collapse
Affiliation(s)
- Gabriela Koifman
- Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel
| | - Ronit Aloni-Grinstein
- Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel.,Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Varda Rotter
- Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel
| |
Collapse
|
|
16
|
Liu Q, Li Q, Zhu S, Yi Y, Cao Q. B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer. Asian J Androl 2020; 21:224-232. [PMID: 29862993 PMCID: PMC6498728 DOI: 10.4103/aja.aja_38_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
Collapse
Affiliation(s)
- Qipeng Liu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Xiangya School of Medicine, Central South University, Changsha 410008, China
| | - Qiaqia Li
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Xiangya School of Medicine, Central South University, Changsha 410008, China
| | - Sen Zhu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Yang Yi
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China.,Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qi Cao
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA.,Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA
| |
Collapse
|
|
17
|
Bahmad HF, Poppiti RJ. Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets. J Clin Pathol 2020; 73:243-249. [PMID: 32034059 DOI: 10.1136/jclinpath-2019-206246] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/12/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
Medulloblastoma (MB) is the most common malignant primary intracranial neoplasm diagnosed in childhood. Although numerous efforts have been made during the past few years to exploit novel targeted therapies for this aggressive neoplasm, there still exist substantial hitches hindering successful management of MB. Lately, progress in cancer biology has shown evidence that a subpopulation of cells within the tumour, namely cancer stem cells (CSCs), are thought to be responsible for the resistance to most chemotherapeutic agents and radiation therapy, accounting for cancer recurrence. Hence, it is crucial to identify the molecular signatures and genetic aberrations that characterise those CSCs and develop therapies that specifically target them. In this review, we aim to give an overview of the main genetic and molecular cues that depict MB-CSCs and provide a synopsis of the novel therapeutic approaches that specifically target this population of cells to attain enhanced antitumorous effects and therefore overcome resistance to therapy.
Collapse
Affiliation(s)
- Hisham F Bahmad
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA.,Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Robert J Poppiti
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA .,Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
| |
Collapse
|
|
18
|
Modeling Late-Onset Sporadic Alzheimer's Disease through BMI1 Deficiency. Cell Rep 2019; 23:2653-2666. [PMID: 29847796 DOI: 10.1016/j.celrep.2018.04.097] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 02/20/2018] [Accepted: 04/24/2018] [Indexed: 12/31/2022] Open
Abstract
Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD.
Collapse
|
|
19
|
Hu X, Zheng W, Zhu Q, Gu L, Du Y, Han Z, Zhang X, Carter DR, Cheung BB, Qiu A, Jiang C. Increase in DNA Damage by MYCN Knockdown Through Regulating Nucleosome Organization and Chromatin State in Neuroblastoma. Front Genet 2019; 10:684. [PMID: 31396265 PMCID: PMC6667652 DOI: 10.3389/fgene.2019.00684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/01/2019] [Indexed: 11/25/2022] Open
Abstract
As a transcription factor, MYCN regulates myriad target genes including the histone chaperone FACT. Moreover, FACT and MYCN expression form a forward feedback loop in neuroblastoma. It is unclear whether MYCN is involved in chromatin remodeling in neuroblastoma through regulation of its target genes. We showed here that MYCN knockdown resulted in loss of the nucleosome-free regions through nucleosome assembly in the promoters of genes functionally enriched for DNA repair. The active mark H3K9ac was removed or replaced by the repressive mark H3K27me3 in the promoters of double-strand break repair-related genes upon MYCN knockdown. Such chromatin state alterations occurred only in MYCN-bound promoters. Consistently, MYCN knockdown resulted in a marked increase in DNA damage in the treatment with hydroxyurea. In contrast, nucleosome reorganization and histone modification changes in the enhancers largely included target genes with tumorigenesis-related functions such as cell proliferation, cell migration, and cell–cell adhesion. The chromatin state significantly changed in both MYCN-bound and MYCN-unbound enhancers upon MYCN knockdown. Furthermore, MYCN knockdown independently regulated chromatin remodeling in the promoters and the enhancers. These findings reveal the novel epigenetic regulatory role of MYCN in chromatin remodeling and provide an alternative potential epigenetic strategy for MYCN-driven neuroblastoma treatment.
Collapse
Affiliation(s)
- Xinjie Hu
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China
| | - Weisheng Zheng
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China
| | - Qianshu Zhu
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China
| | - Liang Gu
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China
| | - Yanhua Du
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China
| | - Zhe Han
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China
| | - Xiaobai Zhang
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China
| | - Daniel R Carter
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, UNSW Sydney, Randwick, NSW, Australia.,School of Biomedical Engineering, University of Technology, Sydney, NSW, Australia
| | - Belamy B Cheung
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, UNSW Sydney, Randwick, NSW, Australia
| | - Andong Qiu
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China.,The Research Center of Stem Cells and Ageing, Tsingtao Advanced Research Institute, Tongji University, Tsingdao, China
| | - Cizhong Jiang
- Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China.,The Research Center of Stem Cells and Ageing, Tsingtao Advanced Research Institute, Tongji University, Tsingdao, China
| |
Collapse
|
|
20
|
Bahmad HF, Chamaa F, Assi S, Chalhoub RM, Abou-Antoun T, Abou-Kheir W. Cancer Stem Cells in Neuroblastoma: Expanding the Therapeutic Frontier. Front Mol Neurosci 2019; 12:131. [PMID: 31191243 PMCID: PMC6546065 DOI: 10.3389/fnmol.2019.00131] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor often diagnosed in childhood. Despite intense efforts to develop a successful treatment, current available therapies are still challenged by high rates of resistance, recurrence and progression, most notably in advanced cases and highly malignant tumors. Emerging evidence proposes that this might be due to a subpopulation of cancer stem cells (CSCs) or tumor-initiating cells (TICs) found in the bulk of the tumor. Therefore, the development of more targeted therapy is highly dependent on the identification of the molecular signatures and genetic aberrations characteristic to this subpopulation of cells. This review aims at providing an overview of the key molecular players involved in NB CSCs and focuses on the experimental evidence from NB cell lines, patient-derived xenografts and primary tumors. It also provides some novel approaches of targeting multiple drivers governing the stemness of CSCs to achieve better anti-tumor effects than the currently used therapeutic agents.
Collapse
Affiliation(s)
- Hisham F Bahmad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Farah Chamaa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Sahar Assi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Reda M Chalhoub
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Tamara Abou-Antoun
- Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese American University, Byblos, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| |
Collapse
|
|
21
|
Abstract
PURPOSE OF REVIEW Childhood blastomas, unlike adult cancers, originate from developing organs in which molecular and cellular features exhibit differentiation arrest and embryonic characteristics. Conventional cancer therapies, which rely on the generalized cytotoxic effect on rapidly dividing cells, may damage delicate organs in young children, leading to multiple late effects. Deep understanding of the biology of embryonal cancers is crucial in reshaping the cancer treatment paradigm for children. RECENT FINDINGS p53 plays a major physiological role in embryonic development, by controlling cell proliferation, differentiation and responses to cellular stress. Tumor suppressor function of p53 is commonly lost in adult cancers through genetic alterations. However, both somatic and germline p53 mutations are rare in childhood blastomas, suggesting that in these cancers, p53 may be inactivated through other mechanisms than mutation. In this review, we summarize current knowledge about p53 pathway inactivation in childhood blastomas (specifically neuroblastoma, retinoblastoma and Wilms' tumor) through various upstream mechanisms. Laboratory evidence and clinical trials of targeted therapies specific to exploiting p53 upstream regulators are discussed. SUMMARY Despite the low rate of inherent TP53 mutations, p53 pathway inactivation is a common denominator in childhood blastomas. Exploiting p53 and its regulators is likely to translate into more effective targeted therapies with minimal late effects for children. (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/COON/A23).
Collapse
Affiliation(s)
- Lixian Oh
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia
| | - Hind Hafsi
- Institute of Advanced Biosciences, University of Grenoble-Alpes, La Tronche, France
| | - Pierre Hainaut
- Institute of Advanced Biosciences, University of Grenoble-Alpes, La Tronche, France
| | - Hany Ariffin
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
22
|
El Hajjar J, Chatoo W, Hanna R, Nkanza P, Tétreault N, Tse YC, Wong TP, Abdouh M, Bernier G. Heterochromatic genome instability and neurodegeneration sharing similarities with Alzheimer's disease in old Bmi1+/- mice. Sci Rep 2019; 9:594. [PMID: 30679733 PMCID: PMC6346086 DOI: 10.1038/s41598-018-37444-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 11/30/2018] [Indexed: 11/15/2022] Open
Abstract
Sporadic Alzheimer’s disease (AD) is the most common cause of dementia. However, representative experimental models of AD have remained difficult to produce because of the disease’s uncertain origin. The Polycomb group protein BMI1 regulates chromatin compaction and gene silencing. BMI1 expression is abundant in adult brain neurons but down-regulated in AD brains. We show here that mice lacking one allele of Bmi1 (Bmi1+/−) develop normally but present with age cognitive deficits and neurodegeneration sharing similarities with AD. Bmi1+/− mice also transgenic for the amyloid beta precursor protein died prematurely and present aggravated disease. Loss of heterochromatin and DNA damage response (DDR) at repetitive DNA sequences were predominant in Bmi1+/− mouse neurons and inhibition of the DDR mitigated the amyloid and Tau phenotype. Heterochromatin anomalies and DDR at repetitive DNA sequences were also found in AD brains. Aging Bmi1+/− mice may thus represent an interesting model to identify and study novel pathogenic mechanisms related to AD.
Collapse
Affiliation(s)
- Jida El Hajjar
- Stem Cell and Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada
| | - Wassim Chatoo
- Stem Cell and Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada
| | - Roy Hanna
- Stem Cell and Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada
| | - Patrick Nkanza
- Stem Cell and Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada
| | - Nicolas Tétreault
- Stem Cell and Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada
| | - Yiu Chung Tse
- Department of Psychiatry, McGill University, Montreal, Canada.,Douglas Mental Health University Institute, Montreal, Canada
| | - Tak Pan Wong
- Department of Psychiatry, McGill University, Montreal, Canada.,Douglas Mental Health University Institute, Montreal, Canada
| | - Mohamed Abdouh
- Stem Cell and Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada
| | - Gilbert Bernier
- Stem Cell and Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada. .,Department of Neurosciences, University of Montreal, Montreal, Canada.
| |
Collapse
|
|
23
|
Karimi Mazraehshah M, Tavangar SM, Saidijam M, Amini R, Bahreini F, Karimi Dermani F, Najafi R. Anticancer effects of miR-200c in colorectal cancer through BMI1. J Cell Biochem 2018; 119:10005-10012. [PMID: 30171714 DOI: 10.1002/jcb.27330] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/28/2018] [Indexed: 01/03/2023]
Abstract
Colorectal cancer (CRC) is one of the most leading cancer deaths throughout the world. MiR-200c has been shown to have a critical role in cancer initiation and progression. In this study, we investigated the miR-200c expression in CRC tissues and its effects on CRC cell lines which were mediated by polycomb complex protein (BMI1). Quantitative reverse transcription polymerase chain reaction (QRT-PCR) and immunohistochemistry were used to detect miR-200c and BMI1 expression in tumor tissues from 38 patients with CRC and 38 normal colon tissues. HCT-116 and SW-48 cells were transfected by locked nucleic acid (LNA)-anti-miR-200c. Western blot analysis and real-time PCR were applied to determine the BMI1 protein and microRNA (miRNA) levels. The apoptosis was analyzed via annexin/propidium iodide staining, and cell invasion was evaluated by transwell assay. MiR-200c was markedly downregulated in CRC tissues, whereas the protein expression of BMI1 in CRC tissues was upregulated compared with normal colon tissues. In the colon cancer cell lines, transfection of LNA-anti-miR-200c increased BMI1 gene and protein expression as well as the cell invasion. Downregulation of miR-200c by LNA decreased the apoptotic cells. The results from this study revealed that miR-200c may have antitumor effects through inhibition of BMI1 expression.
Collapse
Affiliation(s)
| | - Seyed Mohammad Tavangar
- Department of Pathology, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Amini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Bahreini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Karimi Dermani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| |
Collapse
|
|
24
|
Ooi CY, Carter DR, Liu B, Mayoh C, Beckers A, Lalwani A, Nagy Z, De Brouwer S, Decaesteker B, Hung TT, Norris MD, Haber M, Liu T, De Preter K, Speleman F, Cheung BB, Marshall GM. Network Modeling of microRNA-mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN. Cancer Res 2018; 78:3122-3134. [PMID: 29610116 DOI: 10.1158/0008-5472.can-17-3034] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 02/07/2018] [Accepted: 03/28/2018] [Indexed: 11/16/2022]
Abstract
Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. On the basis of a Bayesian learning network model in which we compared pretumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA-mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo Together, these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis.Significance: Network modeling of miRNA-mRNA regulatory interactions in a mouse model of neuroblastoma identifies miR-204 as a tumor suppressor and negative regulator of MYCN. Cancer Res; 78(12); 3122-34. ©2018 AACR.
Collapse
Affiliation(s)
- Chi Yan Ooi
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia
| | - Daniel R Carter
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia.,School of Women's & Children's Health, University of New South Wales Australia, Randwick, New South Wales, Australia
| | - Bing Liu
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia
| | - Chelsea Mayoh
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia
| | - Anneleen Beckers
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), Ghent, Belgium
| | - Amit Lalwani
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia
| | - Zsuzsanna Nagy
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia
| | - Sara De Brouwer
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), Ghent, Belgium
| | - Bieke Decaesteker
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), Ghent, Belgium
| | - Tzong-Tyng Hung
- Biological Resource Imaging Laboratory, the University of New South Wales, Kensington, New South Wales, Australia
| | - Murray D Norris
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia.,Centre for Childhood Cancer Research, University of New South Wales, Randwick, New South Wales, Australia
| | - Michelle Haber
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia
| | - Tao Liu
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia
| | - Katleen De Preter
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), Ghent, Belgium
| | - Frank Speleman
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), Ghent, Belgium
| | - Belamy B Cheung
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia. .,School of Women's & Children's Health, University of New South Wales Australia, Randwick, New South Wales, Australia
| | - Glenn M Marshall
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia. .,School of Women's & Children's Health, University of New South Wales Australia, Randwick, New South Wales, Australia.,Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia
| |
Collapse
|
|
25
|
The putative tumor suppressor gene EphA7 is a novel BMI-1 target. Oncotarget 2018; 7:58203-58217. [PMID: 27533460 PMCID: PMC5295425 DOI: 10.18632/oncotarget.11279] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 08/08/2016] [Indexed: 11/25/2022] Open
Abstract
Bmi1 was originally identified as a gene that contributes to the development of mouse lymphoma by inhibiting MYC-induced apoptosis through repression of Ink4a and Arf. It codes for the Polycomb group protein BMI-1 and acts primarily as a transcriptional repressor via chromatin modifications. Although it binds to a large number of genomic regions, the direct BMI-1 target genes described so far do not explain the full spectrum of BMI-1-mediated effects. Here we identify the putative tumor suppressor gene EphA7 as a novel direct BMI-1 target in neural cells and lymphocytes. EphA7 silencing has been reported in several different human tumor types including lymphomas, and our data suggest BMI1 overexpression as a novel mechanism leading to EphA7 inactivation via H3K27 trimethylation and DNA methylation.
Collapse
|
|
26
|
Zang J, Hui L, Yang N, Yang B, Jiang X. Downregulation of MiR-203a Disinhibits Bmi1 and Promotes Growth and Proliferation of Keratinocytes in Cholesteatoma. Int J Med Sci 2018; 15:447-455. [PMID: 29559833 PMCID: PMC5859767 DOI: 10.7150/ijms.22410] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 02/04/2018] [Indexed: 11/24/2022] Open
Abstract
Background: Keratinocytes are the predominant cell type in a cholesteatoma, and microRNA (miR)-203a has been shown to be essential for the growth and differentiation of keratinocytes. The regulatory mechanisms of miR-203a and Bmi1-the predicted target of miR-203a that is associated with cholesteatoma-have not been clarified. Methods: Real-time PCR and western blot were carried out for the detection of miRNAs, mRNAs, and proteins, including miR-203a, Bmi1, and phosphorylated (p-)Akt. Immunohistochemical staining was applied to observe the expression and distribution of Bmi1 and of p-Akt in cholesteatoma and in control retroauricular skin. The dual luciferase reporter assay was used to analyze the relationship between miR-203a and Bmi1. Ectopic miR-203a and Bmi1 were transfected into an immortalized line of human keratinocytes (HaCaT cells), and the roles of these molecules in cell proliferation, apoptosis, and migration were explored. Results: Cholesteatoma tissues were characterized by downregulation of miR-203a and concomitant upregulation of Bmi1. Results of the dual-luciferase reporter assay indicated that Bmi1 was a direct target gene of miR-203a. Silencing of miR-203a increased Bmi1 expression; promoted proliferation, colony formation, and migration of HaCaT cells; and inhibited apoptosis. Moreover, p-Akt was significantly increased in cholesteatoma tissues and was positively correlated with Bmi1. Suppression of Bmi1 reduced p-Akt expression in HaCaT cells; subsequent inhibition of miR-203a reversed this phenomenon. Conclusions: Our results reveal that miR-203a may regulate cholesteatoma growth and proliferation by targeting Bmi1. These findings provide insight for the development of novel nonsurgical options for cholesteatoma.
Collapse
Affiliation(s)
- Jian Zang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Lian Hui
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Ning Yang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Bo Yang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Xuejun Jiang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| |
Collapse
|
|
27
|
Yi J, Wu J. Epigenetic regulation in medulloblastoma. Mol Cell Neurosci 2017; 87:65-76. [PMID: 29269116 DOI: 10.1016/j.mcn.2017.09.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 09/08/2017] [Accepted: 09/10/2017] [Indexed: 12/14/2022] Open
Abstract
Medulloblastoma is the most common malignant childhood brain tumor. The heterogeneous tumors are classified into four subgroups based on transcription profiles. Recent developments in genome-wide sequencing techniques have rapidly advanced the understanding of these tumors. The high percentages of somatic alterations of genes encoding chromatin regulators in all subgroups suggest that epigenetic deregulation is a major driver of medulloblastoma. In this report, we review the current understanding of epigenetic regulation in medulloblastoma with a focus on the functional studies of chromatin regulators in the initiation and progression of specific subgroups of medulloblastoma. We also discuss the potential usage of epigenetic inhibitors for medulloblastoma treatment.
Collapse
Affiliation(s)
- Jiaqing Yi
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA
| | - Jiang Wu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA.
| |
Collapse
|
|
28
|
Shen J, Li P, Shao X, Yang Y, Liu X, Feng M, Yu Q, Hu R, Wang Z. The E3 Ligase RING1 Targets p53 for Degradation and Promotes Cancer Cell Proliferation and Survival. Cancer Res 2017; 78:359-371. [PMID: 29187402 DOI: 10.1158/0008-5472.can-17-1805] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 10/11/2017] [Accepted: 11/21/2017] [Indexed: 11/16/2022]
Abstract
As a component of the transcriptional repression complex 1 (PRC1), the ring finger protein RING1 participates in the epigenetic regulation in cancer. However, the contributions of RING1 to cancer etiology or development are unknown. In this study, we report that RING1 is a critical negative regulator of p53 homeostasis in human hepatocellular and colorectal carcinomas. RING1 acts as an E3 ubiquitin (Ub) ligase to directly interact with and ubiquitinate p53, resulting in its proteasome-dependent degradation. The RING domain of RING1 was required for its E3 Ub ligase activity. RING1 depletion inhibited the proliferation and survival of the p53 wild-type cancer cells by inducing cell-cycle arrest, apoptosis, and senescence, with only modest effects on p53-deficient cells. Its growth inhibitory effect was partially rescued by p53 silencing, suggesting an important role for the RING1-p53 complex in human cancer. In clinical specimens of hepatocellular carcinoma, RING1 upregulation was evident in association with poor clinical outcomes. Collectively, our results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer.Significance: These results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer. Cancer Res; 78(2); 359-71. ©2017 AACR.
Collapse
Affiliation(s)
- Jiajia Shen
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pengyu Li
- Qilu Hospital of Shandong University, Jinan, China
| | - Xuejing Shao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yang Yang
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
| | - Xiujun Liu
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Feng
- Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Biopolis, Singapore
| | - Qiang Yu
- Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Biopolis, Singapore
| | - Ronggui Hu
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
| | - Zhen Wang
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
29
|
Nishida Y, Maeda A, Kim MJ, Cao L, Kubota Y, Ishizawa J, AlRawi A, Kato Y, Iwama A, Fujisawa M, Matsue K, Weetall M, Dumble M, Andreeff M, Davis TW, Branstrom A, Kimura S, Kojima K. The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells. Blood Cancer J 2017; 7:e527. [PMID: 28211885 PMCID: PMC5386342 DOI: 10.1038/bcj.2017.8] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 12/20/2016] [Indexed: 12/24/2022] Open
Abstract
Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization. PTC596 induced apoptosis in a p53-independent manner. PTC596 induced apoptosis along with the reduction of MCL-1 and phosphorylated AKT in patient-derived CD34+CD38low/− stem/progenitor cells. Mouse xenograft models demonstrated in vivo anti-leukemia activity of PTC596, which inhibited leukemia cell growth in vivo while sparing normal hematopoietic cells. Our results indicate that PTC596 deserves further evaluation in clinical trials for refractory or relapsed AML patients, especially for those with unfavorable complex karyotype or therapy-related AML that are frequently associated with p53 mutations.
Collapse
Affiliation(s)
- Y Nishida
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan
| | - A Maeda
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan
| | - M J Kim
- PTC Therapeutics, South Plainfield, NJ, USA
| | - L Cao
- PTC Therapeutics, South Plainfield, NJ, USA
| | - Y Kubota
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan
| | - J Ishizawa
- Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - A AlRawi
- Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Y Kato
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A Iwama
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - M Fujisawa
- Division of Hematology/Oncology, Department of Medicine, Kameda Medical Center, Kamogawa, Japan
| | - K Matsue
- Division of Hematology/Oncology, Department of Medicine, Kameda Medical Center, Kamogawa, Japan
| | - M Weetall
- PTC Therapeutics, South Plainfield, NJ, USA
| | - M Dumble
- Bristol-Myers Squibb, Princeton, NJ, USA
| | - M Andreeff
- Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - T W Davis
- PMV Pharmaceuticals Inc., Cranbury, NJ, USA
| | | | - S Kimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan
| | - K Kojima
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan
| |
Collapse
|
|
30
|
Carter DR, Murray J, Cheung BB, Gamble L, Koach J, Tsang J, Sutton S, Kalla H, Syed S, Gifford AJ, Issaeva N, Biktasova A, Atmadibrata B, Sun Y, Sokolowski N, Ling D, Kim PY, Webber H, Clark A, Ruhle M, Liu B, Oberthuer A, Fischer M, Byrne J, Saletta F, Thwe LM, Purmal A, Haderski G, Burkhart C, Speleman F, De Preter K, Beckers A, Ziegler DS, Liu T, Gurova KV, Gudkov AV, Norris MD, Haber M, Marshall GM. Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma. Sci Transl Med 2016; 7:312ra176. [PMID: 26537256 DOI: 10.1126/scitranslmed.aab1803] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.
Collapse
Affiliation(s)
- Daniel R Carter
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. School of Women's and Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia
| | - Jayne Murray
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Belamy B Cheung
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. School of Women's and Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia
| | - Laura Gamble
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Jessica Koach
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Joanna Tsang
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Selina Sutton
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Heyam Kalla
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Sarah Syed
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Andrew J Gifford
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. Department of Anatomical Pathology (SEALS), Prince of Wales Hospital, Randwick, New South Wales 2031, Australia
| | - Natalia Issaeva
- Department of Surgery, Otolaryngology, and Yale Cancer Center, Yale University, New Haven, CT 06511, USA
| | - Asel Biktasova
- Department of Surgery, Otolaryngology, and Yale Cancer Center, Yale University, New Haven, CT 06511, USA
| | - Bernard Atmadibrata
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Yuting Sun
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Nicolas Sokolowski
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Dora Ling
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Patrick Y Kim
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Hannah Webber
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Ashleigh Clark
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Michelle Ruhle
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - Bing Liu
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia
| | - André Oberthuer
- Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, 50931 Cologne, Germany. Department of Neonatology and Pediatric Intensive Care Medicine, Children's Hospital, University of Cologne, 50931 Cologne, Germany
| | - Matthias Fischer
- Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, 50931 Cologne, Germany. Max Planck Institute for Metabolism Research, 50931 Cologne, Germany
| | - Jennifer Byrne
- Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia. University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia
| | - Federica Saletta
- Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia
| | - Le Myo Thwe
- Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia. University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia
| | | | | | | | - Frank Speleman
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium
| | - Katleen De Preter
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium
| | - Anneleen Beckers
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium
| | - David S Ziegler
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. School of Women's and Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales 2031, Australia
| | - Tao Liu
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium
| | - Katerina V Gurova
- Incuron, LLC, Buffalo, NY 14203, USA. Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Andrei V Gudkov
- Incuron, LLC, Buffalo, NY 14203, USA. Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Murray D Norris
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. University of New South Wales Centre for Childhood Cancer Research, Randwick, New South Wales 2031, Australia
| | - Michelle Haber
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
| | - Glenn M Marshall
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales 2031, Australia.
| |
Collapse
|
|
31
|
Carter DR, Sutton SK, Pajic M, Murray J, Sekyere EO, Fletcher J, Beckers A, De Preter K, Speleman F, George RE, Haber M, Norris MD, Cheung BB, Marshall GM. Glutathione biosynthesis is upregulated at the initiation of MYCN-driven neuroblastoma tumorigenesis. Mol Oncol 2016; 10:866-78. [PMID: 26996379 DOI: 10.1016/j.molonc.2016.02.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 02/11/2016] [Accepted: 02/19/2016] [Indexed: 10/22/2022] Open
Abstract
The MYCN gene is amplified and overexpressed in a large proportion of high stage neuroblastoma patients and has been identified as a key driver of tumorigenesis. However, the mechanism by which MYCN promotes tumor initiation is poorly understood. Here we conducted metabolic profiling of pre-malignant sympathetic ganglia and tumors derived from the TH-MYCN mouse model of neuroblastoma, compared to non-malignant ganglia from wildtype littermates. We found that metabolites involved in the biosynthesis of glutathione, the most abundant cellular antioxidant, were the most significantly upregulated metabolic pathway at tumor initiation, and progressively increased to meet the demands of tumorigenesis. A corresponding increase in the expression of genes involved in ribosomal biogenesis suggested that MYCN-driven transactivation of the protein biosynthetic machinery generated the necessary substrates to drive glutathione biosynthesis. Pre-malignant sympathetic ganglia from TH-MYCN mice had higher antioxidant capacity and required glutathione upregulation for cell survival, when compared to wildtype ganglia. Moreover, in vivo administration of inhibitors of glutathione biosynthesis significantly delayed tumorigenesis when administered prophylactically and potentiated the anticancer activity of cytotoxic chemotherapy against established tumors. Together these results identify enhanced glutathione biosynthesis as a selective metabolic adaptation required for initiation of MYCN-driven neuroblastoma, and suggest that glutathione-targeted agents may be used as a potential preventative strategy, or as an adjuvant to existing chemotherapies in established disease.
Collapse
Affiliation(s)
- Daniel R Carter
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; School of Women's & Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia
| | - Selina K Sutton
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia
| | - Marina Pajic
- The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia
| | - Jayne Murray
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia
| | - Eric O Sekyere
- Endeavour College of Natural Health, Sydney, 2000, Australia
| | - Jamie Fletcher
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia
| | - Anneleen Beckers
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium
| | - Katleen De Preter
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium
| | - Frank Speleman
- Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium
| | - Rani E George
- Department of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michelle Haber
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia
| | - Murray D Norris
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; University of New South Wales, Centre for Childhood Cancer Research, Randwick, New South Wales 2031, Australia
| | - Belamy B Cheung
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; School of Women's & Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia.
| | - Glenn M Marshall
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, Australia.
| |
Collapse
|
|
32
|
Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice. Biol Psychiatry 2015; 78:848-59. [PMID: 25792222 PMCID: PMC4532653 DOI: 10.1016/j.biopsych.2015.02.004] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 02/03/2015] [Accepted: 02/04/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders. METHODS RNA sequencing was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time quantitative polymerase chain reaction and a candidate lncRNA, Gomafu, was selected for further investigation. The functional role of this schizophrenia-related lncRNA was explored in vivo by antisense oligonucleotide-mediated gene knockdown in the medial prefrontal cortex, followed by behavioral training and assessment of fear-related anxiety. Long noncoding RNA-directed epigenetic regulation of gene expression was investigated by chromatin and RNA immunoprecipitation assays. RESULTS RNA sequencing analysis revealed changes in the expression of a significant number of genes related to neural plasticity and stress, as well as the dynamic regulation of lncRNAs. In particular, we detected a significant downregulation of Gomafu lncRNA. Our results revealed that Gomafu plays a role in mediating anxiety-like behavior and suggest that this may occur through an interaction with a key member of the polycomb repressive complex 1, BMI1, which regulates the expression of the schizophrenia-related gene beta crystallin (Crybb1). We also demonstrated a novel role for Crybb1 in mediating fear-induced anxiety-like behavior. CONCLUSIONS Experience-dependent expression of lncRNAs plays an important role in the epigenetic regulation of adaptive behavior, and the perturbation of Gomafu may be related to anxiety and the development of neuropsychiatric disorders.
Collapse
|
|
33
|
Jin Y, Wang H, Han W, Lu J, Chu P, Han S, Ni X, Ning B, Yu D, Guo Y. Single nucleotide polymorphism rs11669203 in TGFBR3L is associated with the risk of neuroblastoma in a Chinese population. Tumour Biol 2015; 37:3739-47. [PMID: 26468016 DOI: 10.1007/s13277-015-4192-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/01/2015] [Indexed: 12/31/2022] Open
Abstract
With a primary mortality, neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Amplification of the MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog) oncogene is observed in 20-30 % of NB cases, a feature which also characterizes a highly aggressive subtype of the disease. However, the systematic study of association between single nucleotide polymorphisms (SNPs) in MYCN-regulated genes and the risk of NB has not been investigated. In the current study, we scanned a set of 16 SNPs located within known or predicted MYCN binding sites in a cohort of 247 patients of Chinese origin with neuroblastic family tumors, including neuroblastoma (NB), ganglioneuroma (GN), and ganglioneuroblastoma (GNB), and in 290 cancer-free controls to determine whether any of the tested SNPs are associated with neuroblastic family tumors. We found that the rs11669203 G>C polymorphism, located in TGFBR3L promoter, is significantly associated with the risk of NB. Further, we found that this association is site specific to adrenal NB compared to non-adrenal NB. In addition, transcriptome analysis indicated that increased expression of TGFBR3L is strongly correlated with poor survival. The SNP rs11669203 located at the MYCN binding site of TGFBR3L is significantly associated with elevated risk of NB, and abnormal MYCN-regulated TGFBR3L expression may contribute to NB oncogenesis.
Collapse
Affiliation(s)
- Yaqiong Jin
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Huanmin Wang
- Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Wei Han
- Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Jie Lu
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Ping Chu
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Shujing Han
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Xin Ni
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
- Department of Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Baitang Ning
- National Center for Toxicological Research, US Food and Drug Administration, Jefferson, USA
| | - Dianke Yu
- National Center for Toxicological Research, US Food and Drug Administration, Jefferson, USA.
| | - Yongli Guo
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
34
|
Koo BH, Kim Y, Je Cho Y, Kim DS. Distinct roles of transforming growth factor-β signaling and transforming growth factor-β receptor inhibitor SB431542 in the regulation of p21 expression. Eur J Pharmacol 2015; 764:413-423. [PMID: 26187313 DOI: 10.1016/j.ejphar.2015.07.032] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 07/07/2015] [Accepted: 07/13/2015] [Indexed: 11/23/2022]
Abstract
Transforming growth factor-β (TGF-β) has both tumor suppressive and oncogenic activities. Autocrine TGF-β signaling supports tumor survival and growth in certain types of cancer, and the TGF-β signaling pathway is a potential therapeutic target for these types of cancer. TGF-β induces p21 expression, and p21 is considered as an oncogene as well as a tumor suppressor, due to its anti-apoptotic activity. Thus, we hypothesized that autocrine TGF-β signaling maintains the expression of p21 at levels that can support cell growth. To verify this hypothesis, we sought to examine p21 expression and cell growth in various cancer cells following the inhibition of autocrine TGF-β signaling using siRNAs targeting TGF-β signaling components and SB431542, a TGF-β receptor inhibitor. Results from the present study show that p21 expression and cell growth were reduced by knockdown of TGF-β signaling components using siRNA in MDA-MB231 and A549 cells. Cell growth was also reduced in p21 siRNA-transfected cells. Downregulation of p21 expression induced cellular senescence in MDA-MB231 cells but did not induce apoptosis in both cells. These data suggest that autocrine TGF-β signaling is required to sustain p21 levels for positive regulation of cell cycle. On the other hand, treatment with SB431542 up-regulated p21 expression while inhibiting cell growth. The TGF-β signaling pathway was not associated with the SB431542-mediated induction of p21 expression. Specificity protein 1 (Sp1) was downregulated by treatment with SB431542, and p21 expression was increased by Sp1 knockdown. These findings suggest that downregulation of Sp1 expression is responsible for SB43154-induced p21 expression.
Collapse
Affiliation(s)
- Bon-Hun Koo
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea.
| | - Yeaji Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea.
| | - Yang Je Cho
- R & D Center, EyeGene Inc., Seoul 120-113, Republic of Korea.
| | - Doo-Sik Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea.
| |
Collapse
|
|
35
|
Arsenic toxi-RNomics has the ability to tailor the host immune response. Exp Mol Pathol 2015; 99:360-4. [DOI: 10.1016/j.yexmp.2015.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 08/18/2015] [Indexed: 11/18/2022]
|
|
36
|
Cheung BB, Tan O, Koach J, Liu B, Shum MSY, Carter DR, Sutton S, Po'uha ST, Chesler L, Haber M, Norris MD, Kavallaris M, Liu T, O'Neill GM, Marshall GM. Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma. Mol Oncol 2015; 9:1484-500. [PMID: 25963741 PMCID: PMC5528804 DOI: 10.1016/j.molonc.2015.04.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 04/17/2015] [Accepted: 04/17/2015] [Indexed: 10/23/2022] Open
Abstract
Retinoids are an important component of neuroblastoma therapy at the stage of minimal residual disease, yet 40-50% of patients treated with 13-cis-retinoic acid (13-cis-RA) still relapse, indicating the need for more effective retinoid therapy. Vorinostat, or Suberoylanilide hydroxamic acid (SAHA), is a potent inhibitor of histone deacetylase (HDAC) classes I & II and has antitumor activity in vitro and in vivo. Fenretinide (4-HPR) is a synthetic retinoid which acts on cancer cells through both nuclear retinoid receptor and non-receptor mechanisms. In this study, we found that the combination of 4-HPR + SAHA exhibited potent cytotoxic effects on neuroblastoma cells, much more effective than 13-cis-RA + SAHA. The 4-HPR + SAHA combination induced caspase-dependent apoptosis through activation of caspase 3, reduced colony formation and cell migration in vitro, and tumorigenicity in vivo. The 4-HPR and SAHA combination significantly increased mRNA expression of thymosin-beta-4 (Tβ4) and decreased mRNA expression of retinoic acid receptor α (RARα). Importantly, the up-regulation of Tβ4 and down-regulation of RARα were both necessary for the 4-HPR + SAHA cytotoxic effect on neuroblastoma cells. Moreover, Tβ4 knockdown in neuroblastoma cells increased cell migration and blocked the effect of 4-HPR + SAHA on cell migration and focal adhesion formation. In primary human neuroblastoma tumor tissues, low expression of Tβ4 was associated with metastatic disease and predicted poor patient prognosis. Our findings demonstrate that Tβ4 is a novel therapeutic target in neuroblastoma, and that 4-HPR + SAHA is a potential therapy for the disease.
Collapse
Affiliation(s)
- Belamy B Cheung
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia.
| | - Owen Tan
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Jessica Koach
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Bing Liu
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Michael S Y Shum
- Kids Research Institute, Children's Hospital at Westmead, Sydney, Australia
| | - Daniel R Carter
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Selina Sutton
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Sela T Po'uha
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Louis Chesler
- Division of Clinical Studies, Institute of Cancer Research, Sutton, Surrey, UK
| | - Michelle Haber
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Murray D Norris
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Maria Kavallaris
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Tao Liu
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia
| | - Geraldine M O'Neill
- Kids Research Institute, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, University of Sydney, Australia
| | - Glenn M Marshall
- Children's Cancer Institute Australia, University of New South Wales, Sydney, Australia; Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia.
| |
Collapse
|
|
37
|
Kaul D, Sharma S, Garg A. Mitochondrial uncoupling protein (UCP2) gene expression is regulated by miR-2909. Blood Cells Mol Dis 2015; 55:89-93. [PMID: 25976474 DOI: 10.1016/j.bcmd.2015.05.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Revised: 05/03/2015] [Accepted: 05/03/2015] [Indexed: 02/04/2023]
Abstract
Reversible decoupling of glycolysis from aerobic-respiration has been widely recognized to be a crucial step in tailoring immune response by the human cells. In this context, the study reported here revealed for the first time that cooperativity between Apoptosis Antagonizing Transcription Factor (AATF) mRNA and miR-2909 within cellular AATF RNome ensures the regulation of mitochondrial uncoupling protein 2 (UCP2) expression in a cyclic fashion and this phenomenon is substantiated when the immune cells face high glucose threat.
Collapse
Affiliation(s)
- Deepak Kaul
- Department of Experimental Medicine & Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India.
| | - S Sharma
- Department of Experimental Medicine & Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India
| | - A Garg
- Department of Experimental Medicine & Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India
| |
Collapse
|
|
38
|
Bhattacharya R, Mustafi SB, Street M, Dey A, Dwivedi SKD. Bmi-1: At the crossroads of physiological and pathological biology. Genes Dis 2015; 2:225-239. [PMID: 26448339 PMCID: PMC4593320 DOI: 10.1016/j.gendis.2015.04.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells. Despite three decades of research that have elucidated the transcriptional regulation, post-translational modifications and functions of Bmi-1 in regulating the DNA damage response, cellular bioenergetics, and pathologies, the entire potential of a protein with such varied functions remains to be realized. This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer. Additionally, since cancer stem cells are emerging as a new paradigm for therapy resistance, the role of Bmi-1 in this perspective is also highlighted. The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy. Nonetheless, new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.
Collapse
Affiliation(s)
- Resham Bhattacharya
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Soumyajit Banerjee Mustafi
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Mark Street
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Anindya Dey
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Shailendra Kumar Dhar Dwivedi
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| |
Collapse
|
|
39
|
Qiu M, Liang Z, Chen L, Tan G, Wang K, Liu L, Liu J, Chen H. MicroRNA-429 suppresses cell proliferation, epithelial-mesenchymal transition, and metastasis by direct targeting of BMI1 and E2F3 in renal cell carcinoma. Urol Oncol 2015; 33:332.e9-18. [PMID: 25953723 DOI: 10.1016/j.urolonc.2015.03.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 03/16/2015] [Accepted: 03/16/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND MicroRNA-429 (miR-429), a short noncoding RNA belonging to the miR-200 superfamily, plays a crucial role in tumorigenesis and tumor progression. It also acts as a modulator of epithelial-to-mesenchymal transition, a cell development regulating process that affects tumor development and metastasis. The aim of this study was to investigate the potential role of miR-429 in regulating growth and metastasis of renal cell carcinoma. METHODS miR-429 expression was stably up-regulated or down-regulated in the renal cell carcinoma ACHN and A498 cell lines, and cell proliferation and metastasis were assessed. RESULTS miR-429 overexpression inhibited cell proliferation, colony formation, migration, and invasion. Suppression of endogenous miR-429 promoted cell growth and metastasis. miR-429 was shown to directly target the 3' untranslated regions of B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) and E2F transcription factor 3 (E2F3) transcripts, regulating their expression, as well as that of the downstream epithelial-to-mesenchymal transition markers E-cadherin, N-cadherin, vimentin, p14, and p16. CONCLUSIONS These results revealed a tumor suppressive role for miR-429 in renal cell carcinoma through directly targeting BMI1 and E2F3.
Collapse
Affiliation(s)
- Mingning Qiu
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China
| | - Ziji Liang
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China
| | - Lieqian Chen
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China
| | - Guobin Tan
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China
| | - Kangning Wang
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China
| | - Lei Liu
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China
| | - Jianjun Liu
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China.
| | - Hege Chen
- Laboratory of Urology, Guangdong Medical College, Zhanjiang, China.
| |
Collapse
|
|
40
|
High glucose-induced human cellular immune response is governed by miR-2909 RNomics. Blood Cells Mol Dis 2015; 54:342-7. [DOI: 10.1016/j.bcmd.2015.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 01/11/2015] [Indexed: 02/04/2023]
|
|
41
|
Crea F, Nur Saidy NR, Collins CC, Wang Y. The epigenetic/noncoding origin of tumor dormancy. Trends Mol Med 2015; 21:206-11. [PMID: 25771096 DOI: 10.1016/j.molmed.2015.02.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/27/2015] [Accepted: 02/11/2015] [Indexed: 12/13/2022]
Abstract
Cancer stem cells (CSCs) have been implicated as the seeds of treatment resistance and metastasis, which are the most deadly features of a neoplasm. However, an unequivocal definition of the CSC phenotype is still missing. A common feature of normal and aberrant stem cells is their ability to enter a prolonged dormant state. Cancer dormancy is a key mechanism for treatment resistance and metastasis. Here we propose a unified definition of dormancy-competent CSCs (DCCs) as the neoplastic subpopulation that can plastically alternate periods of dormancy and rapid growth. Irreversible DNA mutations can hardly account for this versatile behavior, and based on emerging evidence we propose that cancer dormancy is a nongenetic disease driven by the flexible nature of the epigenetic/noncoding interactome.
Collapse
Affiliation(s)
- Francesco Crea
- Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver, Canada; Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
| | - Nur Ridzwan Nur Saidy
- Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver, Canada; Honours Biotechnology Program, University of British Columbia, Vancouver, Canada
| | - Colin C Collins
- Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - Yuzhuo Wang
- Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver, Canada; Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
| |
Collapse
|
|
42
|
Reynolds JP, Miller-Delaney SFC, Jimenez-Mateos EM, Sano T, McKiernan RC, Simon RP, Henshall DC. Transcriptional Response of Polycomb Group Genes to Status Epilepticus in Mice is Modified by Prior Exposure to Epileptic Preconditioning. Front Neurol 2015; 6:46. [PMID: 25806020 PMCID: PMC4354380 DOI: 10.3389/fneur.2015.00046] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Accepted: 02/23/2015] [Indexed: 12/23/2022] Open
Abstract
Exposure of the brain to brief, non-harmful seizures can activate protective mechanisms that temporarily generate a damage-refractory state. This process, termed epileptic tolerance, is associated with large-scale down-regulation of gene expression. Polycomb group (PcG) proteins are master controllers of gene silencing during development that are re-activated by injury to the brain. Here, we explored the transcriptional response of genes associated with polycomb repressive complex (PRC) 1 (Ring1A, Ring1B, and Bmi1) and PRC2 (Ezh1, Ezh2, and Suz12), as well as additional transcriptional regulators Sirt1, Yy1, and Yy2, in a mouse model of status epilepticus (SE). Findings were contrasted to changes after SE in mice previously given brief seizures to evoke tolerance. Real-time quantitative PCR showed SE prompted an early (1 h) increase in expression of several genes in PRC1 and PRC2 in the hippocampus, followed by down-regulation of many of the same genes at later times points (4, 8, and 24 h). Spatio-temporal differences were found among PRC2 genes in epileptic tolerance, including increased expression of Ezh2, Suz12, and Yy2 relative to the normal injury response to SE. In contrast, PRC1 complex genes including Ring 1B and Bmi1 displayed differential down-regulation in epileptic tolerance. The present study characterizes PcG gene expression following SE and shows prior seizure exposure produces select changes to PRC1 and PRC2 composition that may influence differential gene expression in epileptic tolerance.
Collapse
Affiliation(s)
- James P Reynolds
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland , Dublin , Ireland
| | | | - Eva M Jimenez-Mateos
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland , Dublin , Ireland
| | - Takanori Sano
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland , Dublin , Ireland ; Department of Neurosurgery, Mie University School of Medicine , Tsu, Mie , Japan
| | - Ross C McKiernan
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland , Dublin , Ireland
| | | | - David C Henshall
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland , Dublin , Ireland
| |
Collapse
|
|
43
|
miR-200c inhibits invasion, migration and proliferation of bladder cancer cells through down-regulation of BMI-1 and E2F3. J Transl Med 2014; 12:305. [PMID: 25367080 PMCID: PMC4226852 DOI: 10.1186/s12967-014-0305-z] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 10/21/2014] [Indexed: 12/13/2022] Open
Abstract
Background MicroRNA-200c (miR-200c) is one of the short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression. It also acts as considerable modulator in the process of epithelial-to-mesenchymal transition (EMT), a cell development regulating process that affects tumor development and metastasis. However, the role of miR-200c in bladder cancer cells and its mechanism has not been well studied. The purpose of this study was to determine the potential role of miR-200c in regulating EMT and how it contributed to bladder cancer cells in invasion, migration and proliferation. Methods Real-time reverse transcription-PCR was used to identify and validate the differential expression of MiR-200c involved in EMT in 4 bladder cancer cell lines and clinical specimens. A list of potential miR-200 direct targets was identified through the TargetScan database. The precursor of miR-200c was over-expressed in UMUC-3 and T24 cells using a lentivirus construct, respectively. Protein expression and signaling pathway modulation were validated through Western blot analysis and confocal microscopy, whereas BMI-1 and E2F3, direct target of miR-200c, were validated by using the wild-type and mutant 3′-untranslated region BMI-1/E2F3 luciferase reporters. Results We demonstrate that MiR-200c is down-regulated in bladder cancer specimens compared with adjacent ones in the same patient. Luciferase assays showed that the direct down-regulation of BMI-1 and E2F3 were miR-200c-dependent because mutations in the two putative miR-200c-binding sites have rescued the inhibitory effect. Over-expression of miR-200c in bladder cancer cells resulted in significantly decreased the capacities of cell invasion, migration and proliferation. miR-200c over-expression resulted in conspicuous down-regulation of BMI-1and E2F3 expression and in a concomitant increase in E-cadherin levels. Conclusions miR-200c appears to control the EMT process through BMI-1 in bladder cancer cells, and it inhibits their proliferation through down-regulating E2F3. The targets of miR-200c include BMI-1 and E2F3, which are a novel regulator of EMT and a regulator of proliferation, respectively. Electronic supplementary material The online version of this article (doi:10.1186/s12967-014-0305-z) contains supplementary material, which is available to authorized users.
Collapse
|
|
44
|
Zhang JP, Zhang H, Wang HB, Li YX, Liu GH, Xing S, Li MZ, Zeng MS. Down-regulation of Sp1 suppresses cell proliferation, clonogenicity and the expressions of stem cell markers in nasopharyngeal carcinoma. J Transl Med 2014; 12:222. [PMID: 25099028 PMCID: PMC4132216 DOI: 10.1186/s12967-014-0222-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 07/31/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Transcription factor Sp1 is multifaceted, with the ability to function as an oncogene or a tumor suppressor, depending on the cellular context. We previously reported that Sp1 is required for the transcriptional activation of the key oncogenes in nasopharyngeal carcinoma (NPC), including B-lymphoma mouse Moloney leukemia virus insertion region 1 (Bmi1) and centromere protein H (CENPH), but the role of Sp1 and its underlying mechanisms in NPC remained largely unexplored. The objective of this study was to investigate the cellular function of Sp1 and to verify the clinical significance of Sp1 as a potential therapeutic target in NPC. METHODS The levels of Sp1 in the normal primary nasopharyngeal epithelial cells (NPECs) and NPC cell lines were analyzed by Quantitative Real-time RT-PCR (qRT-PCR) and Western blot. The location and expression of Sp1 in the NPC tissues were detected by immunohistochemistry staining (IHC). The effect of Sp1 knockdown on the cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype in NPC cells were evaluated by MTT, flow cytometry, clonogenicity analysis and sphere formation assay. RESULTS The mRNA and protein levels of Sp1 were elevated in NPC cell lines than in the normal primary NPECs. Higher expression of Sp1 was found in NPC tissues with advanced clinical stage (P=0.00036). Either inhibition of Sp1 activity by mithramycin A, the FDA-approved chemotherapeutic anticancer drug or Sp1 silencing by two distinct siRNA against Sp1 suppressed the growth of NPC cells. Mechanism analysis revealed that Sp1 silencing may suppress cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype through inducing the expression of p27 and p21, and impairing the expressions of the critical stem cell transcription factors (SCTFs), including Bmi1, c-Myc and KLF4 in NPC cells. CONCLUSIONS Sp1 was enriched in advanced NPC tissues and silencing of Sp1 significantly inhibited cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype of NPC cells, suggesting Sp1 may serve as an appealing drug target for NPC.
Collapse
|
|
45
|
Xu XH, Liu XY, Su J, Li DJ, Huang Q, Lu MQ, Yi F, Ren JH, Chen WH. ShRNA targeting Bmi-1 sensitizes CD44⁺ nasopharyngeal cancer stem-like cells to radiotherapy. Oncol Rep 2014; 32:764-70. [PMID: 24927072 DOI: 10.3892/or.2014.3267] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 05/12/2014] [Indexed: 11/06/2022] Open
Abstract
Accumulating evidence indicates that cancer stem cells (CSCs) are involved in resistance to radiation therapy (RT). Bmi-1, a member of the Polycomb family of transcriptional repressors, is essential for maintaining the self-renewal abilities of stem cells and overexpression of Bmi-1 correlates with cancer therapy failure. Our previous study identified that the CD44+ nasopharyngeal cancer (NPC) cells may be assumed as one of markers of nasopharyngeal carcinoma cancer stem cell-like cells (CSC-LCs) and Bmi-1 is overexpressed in CD44+ NPC. In the present study, we used RNA interference technology to knock down the expression of Bmi-1 in CD44+ NPC cells, and then measured the radiation response by clonogenic cell survival assay. DNA repair was monitored by γH2AX foci formation. Bmi-1 downstream relative gene and protein expression of p16, p14, p53 were assessed by western blotting and real-time PCR. Cell cycle and apoptosis were detected by flow cytometry assays. We found that Bmi-1 knockdown prolonged G1 and enhanced the radiation-induced G2/M arrest, inhibited DNA damage repair, elevated protein p16, p14 and p53 expression, leading to increased apoptosis in the radiated CD44+ cells. These data suggest that Bmi-1 downregulation increases the radiosensitivity to CD44+ NPC CSC-LCs. Bmi-1 is a potential target for increasing the sensitivity of NPC CSCs to radiotherapy.
Collapse
Affiliation(s)
- Xin-Hua Xu
- Department of Oncology, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People's Hospital, Yichang, Hubei, P.R. China
| | - Xiao-Yan Liu
- Department of Oncology, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People's Hospital, Yichang, Hubei, P.R. China
| | - Jin Su
- Oncology Institute, China Three Gorges University, Yichang, Hubei, P.R. China
| | - Dao-Jun Li
- Oncology Institute, China Three Gorges University, Yichang, Hubei, P.R. China
| | - Qiao Huang
- Oncology Institute, China Three Gorges University, Yichang, Hubei, P.R. China
| | - Ming-Qian Lu
- Department of Oncology, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People's Hospital, Yichang, Hubei, P.R. China
| | - Fang Yi
- Oncology Institute, China Three Gorges University, Yichang, Hubei, P.R. China
| | - Jing-Hua Ren
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Wei-Hong Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| |
Collapse
|
|
46
|
Cui J, Cheng Y, Zhang P, Sun M, Gao F, Liu C, Cai J. Down Regulation of miR200c Promotes Radiation-Induced Thymic Lymphoma by Targeting BMI1. J Cell Biochem 2014; 115:1033-42. [DOI: 10.1002/jcb.24754] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 12/17/2013] [Indexed: 12/19/2022]
Affiliation(s)
- Jianguo Cui
- Department of Radiation Medicine; Second Military Medical University; Xiangyin Road Shanghai 200433 PR China
| | - Ying Cheng
- Department of Radiation Medicine; Second Military Medical University; Xiangyin Road Shanghai 200433 PR China
| | - Pei Zhang
- Department of Radiation Medicine; Second Military Medical University; Xiangyin Road Shanghai 200433 PR China
| | - Mingjuan Sun
- Department of Biochemistry and Molecular Biology; Second Military Medical University; Xiangyin Road Shanghai 200433 PR China
| | - Fu Gao
- Department of Radiation Medicine; Second Military Medical University; Xiangyin Road Shanghai 200433 PR China
| | - Cong Liu
- Department of Radiation Medicine; Second Military Medical University; Xiangyin Road Shanghai 200433 PR China
| | - Jianming Cai
- Department of Radiation Medicine; Second Military Medical University; Xiangyin Road Shanghai 200433 PR China
| |
Collapse
|
|
47
|
Piunti A, Rossi A, Cerutti A, Albert M, Jammula S, Scelfo A, Cedrone L, Fragola G, Olsson L, Koseki H, Testa G, Casola S, Helin K, di Fagagna FD, Pasini D. Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication. Nat Commun 2014; 5:3649. [PMID: 24728135 PMCID: PMC3996544 DOI: 10.1038/ncomms4649] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 03/13/2014] [Indexed: 12/21/2022] Open
Abstract
The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints.
Collapse
Affiliation(s)
- Andrea Piunti
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
| | - Alessandra Rossi
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
| | - Aurora Cerutti
- IFOM Foundation—FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy
| | - Mareike Albert
- Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark
- Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Sriganesh Jammula
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
| | - Andrea Scelfo
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
| | - Laura Cedrone
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy
| | - Giulia Fragola
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
- IFOM Foundation—FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy
| | - Linda Olsson
- Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark
- Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Haruhiko Koseki
- Developmental Genetics Group, RIKEN Research Center for Allergy & Immunology (RCAI), 1-7-22 Suehiuro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan
| | - Giuseppe Testa
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
| | - Stefano Casola
- IFOM Foundation—FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy
| | - Kristian Helin
- Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark
- Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark
- The Danish Stem Cell Centre, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Fabrizio d’Adda di Fagagna
- IFOM Foundation—FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy
- Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia 27100, Italy
| | - Diego Pasini
- European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy
| |
Collapse
|
|
48
|
Marshall GM, Carter DR, Cheung BB, Liu T, Mateos MK, Meyerowitz JG, Weiss WA. The prenatal origins of cancer. Nat Rev Cancer 2014; 14:277-89. [PMID: 24599217 PMCID: PMC4041218 DOI: 10.1038/nrc3679] [Citation(s) in RCA: 190] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The concept that some childhood malignancies arise from postnatally persistent embryonal cells has a long history. Recent research has strengthened the links between driver mutations and embryonal and early postnatal development. This evidence, coupled with much greater detail on the cell of origin and the initial steps in embryonal cancer initiation, has identified important therapeutic targets and provided renewed interest in strategies for the early detection and prevention of childhood cancer.
Collapse
Affiliation(s)
- Glenn M Marshall
- Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, New South Wales, Australia; and the Children's Cancer Institute Australia for Medical Research, Lowy Cancer Centre, University of New South Wales, Randwick 2031, Australia
| | - Daniel R Carter
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Centre, University of New South Wales, Randwick 2031, Australia
| | - Belamy B Cheung
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Centre, University of New South Wales, Randwick 2031, Australia
| | - Tao Liu
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Centre, University of New South Wales, Randwick 2031, Australia
| | - Marion K Mateos
- Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, New South Wales, Australia; and the Children's Cancer Institute Australia for Medical Research, Lowy Cancer Centre, University of New South Wales, Randwick 2031, Australia
| | - Justin G Meyerowitz
- Department of Neurology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA
| | - William A Weiss
- Department of Neurology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA
| |
Collapse
|
|
49
|
Rivlin N, Koifman G, Rotter V. p53 orchestrates between normal differentiation and cancer. Semin Cancer Biol 2014; 32:10-7. [PMID: 24406212 DOI: 10.1016/j.semcancer.2013.12.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 12/29/2013] [Accepted: 12/30/2013] [Indexed: 12/18/2022]
Abstract
During recent years, it is becoming more and more evident that there is a tight connection between abnormal differentiation processes and cancer. While cancer and stem cells are very different, especially in terms of maintaining genomic integrity, these cell types also share many similar properties. In this review, we aim to provide an over-view of the roles of the key tumor suppressor, p53, in regulating normal differentiation and function of both stem cells and adult cells. When these functions are disrupted, undifferentiated cells may become transformed. Understanding the function of p53 in stem cells and its role in maintaining the balance between differentiation and malignant transformation can help shed light on cancer initiation and propagation, and hopefully also on cancer prevention and therapy.
Collapse
Affiliation(s)
- Noa Rivlin
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
| | - Gabriela Koifman
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Varda Rotter
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| |
Collapse
|
|
50
|
Benetatos L, Vartholomatos G, Hatzimichael E. Polycomb group proteins and MYC: the cancer connection. Cell Mol Life Sci 2014; 71:257-69. [PMID: 23897499 PMCID: PMC11113285 DOI: 10.1007/s00018-013-1426-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 07/12/2013] [Accepted: 07/15/2013] [Indexed: 01/07/2023]
Abstract
Polycomb group proteins (PcGs) are transcriptional repressors involved in physiological processes whereas PcG deregulation might result in oncogenesis. MYC oncogene is able to regulate gene transcription, proliferation, apoptosis, and malignant transformation. MYC deregulation might result in tumorigenesis with tumor maintenance properties in both solid and blood cancers. Although the interaction of PcG and MYC in cancer was described years ago, new findings are reported every day to explain the exact mechanisms and results of such interactions. In this review, we summarize recent data on the PcG and MYC interactions in cancer, and the putative involvement of microRNAs in the equation.
Collapse
Affiliation(s)
- Leonidas Benetatos
- Blood Bank, General Hospital of Preveza, Selefkias 2, 48100, Preveza, Greece,
| | | | | |
Collapse
|