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Wong A, Alejandro EU. Post translational modification regulation of transcription factors governing pancreatic β-cell identity and functional mass. Front Endocrinol (Lausanne) 2025; 16:1562646. [PMID: 40134803 PMCID: PMC11932907 DOI: 10.3389/fendo.2025.1562646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Dysfunction of the insulin-secreting β-cells is a key hallmark of Type 2 diabetes (T2D). In the natural history of the progression of T2D, factors such as genetics, early life exposures, lifestyle, and obesity dictate an individual's susceptibility risk to disease. Obesity is associated with insulin resistance and increased demand for insulin to maintain glucose homeostasis. Studies in both mouse and human islets have implicated the β-cell's ability to compensate through proliferation and survival (increasing functional β-cell mass) as a tipping point toward the development of disease. A growing body of evidence suggests the reduction of β-cell mass in T2D is driven majorly by loss of β-cell identity, rather than by apoptosis alone. The development and maintenance of pancreatic β-cell identity, function, and adaptation to stress is governed, in part, by the spatiotemporal expression of transcription factors (TFs), whose activity is regulated by signal-dependent post-translational modifications (PTM). In this review, we examine the role of these TFs in the developing pancreas and in the mature β-cell. We discuss functional implications of post-translational modifications on these transcription factors' activities and how an understanding of the pathways they regulate can inform therapies to promoteβ-cell regeneration, proliferation, and survival in diabetes.
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Affiliation(s)
- Alicia Wong
- Department of Genetics, Cell Biology, and Development, University of Minnesota Twin Cities, Minneapolis, MN, United States
| | - Emilyn U. Alejandro
- Department of Integrative Biology and Physiology, University of Minnesota Twin Cities, Minneapolis, MN, United States
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2
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Dorando HK, Andrews JM, Borcherding NC, Quinn CC, Schmidt JA, Khatavkar OU, Aluri J, Harmon MT, Watkins MP, Frank A, Cooper MA, Musiek AC, Mehta-Shah N, Payton JE. Single Cell Resolution Tracking of Cutaneous T-Cell Lymphoma Reveals Clonal Evolution in Disease Progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.11.637715. [PMID: 39990420 PMCID: PMC11844462 DOI: 10.1101/2025.02.11.637715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multi-omics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. We present here a comprehensive multi-omics view of CTCL clonal evolution, incorporating exome, whole genome, epigenome, bulk-, single cell (sc) VDJ-, and scRNA-sequencing of 114 clinically annotated serial skin, peripheral blood, and lymph node samples from 35 CTCL patients. We leveraged this extensive dataset to define the molecular underpinnings of CTCL progression in individual patients at single cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified a large number of recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, PI3K signaling, and PD-1 checkpoint pathways as evasion tactics deployed by malignant T cells. We also identified a gain of function mutation in STAT3 (D661Y) and demonstrated by CUT&RUN-seq that it enhances binding to transcription start sites of genes in Rho GTPase pathways, which we previously reported to have activated chromatin and increased expression in HDACi-resistant CTCL. These data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. A striking number of progression-associated mutations occurred in chromatin methylation modifiers, including EZH2, suggesting that EZH1/2 inhibition may also benefit patients with CTCL. Knowledge of these molecular changes should be leveraged for improved disease monitoring, biomarker-informed clinical trial design, and new therapeutic strategies in this challenging and incurable cancer.
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Wozniak M, Czyz M. Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities. Ther Adv Med Oncol 2025; 17:17588359241306026. [PMID: 39776536 PMCID: PMC11705335 DOI: 10.1177/17588359241306026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/21/2024] [Indexed: 01/11/2025] Open
Abstract
The enhancer of zeste homolog 2 (EZH2) is a catalytic component of Polycomb repressive complex 2 (PRC2) mediating the methylation of histone 3 lysine 27 (H3K27me3) and hence the epigenetic repression of target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles that are exerted as PRC2-dependent and PRC2-independent methylation of non-histone proteins, and methyltransferase-independent interactions of EZH2 with various proteins contributing to gene expression regulation and alterations in the protein stability. EZH2 is frequently mutated and/or its expression is deregulated in various cancer types. The cancer sensitivity to inhibitors of EZH2 enzymatic activity and state-of-the-art approaches to deplete EZH2 with chemical degraders are discussed. This review also presents the clinical trials in various phases that evaluate the use of EZH2 inhibitors, both as monotherapy and in combination with other agents for the treatment of patients with diverse types of cancers.
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Affiliation(s)
- Michal Wozniak
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Mazowiecka 6/8, Lodz 92-215, Poland
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Giaimo BD, Ferrante F, Borggrefe T. Lysine and arginine methylation of transcription factors. Cell Mol Life Sci 2024; 82:5. [PMID: 39680066 DOI: 10.1007/s00018-024-05531-6] [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: 09/24/2024] [Revised: 11/09/2024] [Accepted: 11/26/2024] [Indexed: 12/17/2024]
Abstract
Post-translational modifications (PTMs) are implicated in many biological processes including receptor activation, signal transduction, transcriptional regulation and protein turnover. Lysine's side chain is particularly notable, as it can undergo methylation, acetylation, SUMOylation and ubiquitination. Methylation affects not only lysine but also arginine residues, both of which are implicated in epigenetic regulation. Beyond histone-tails as substrates, dynamic methylation of transcription factors has been described. The focus of this review is on these non-histone substrates providing a detailed discussion of what is currently known about methylation of hypoxia-inducible factor (HIF), P53, nuclear receptors (NRs) and RELA. The role of methylation in regulating protein stability and function by acting as docking sites for methyl-reader proteins and via their crosstalk with other PTMs is explored.
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Affiliation(s)
- Benedetto Daniele Giaimo
- Institute of Biochemistry, Justus-Liebig-University Giessen, Friedrichstrasse 24, 35392, Giessen, Germany.
| | - Francesca Ferrante
- Institute of Biochemistry, Justus-Liebig-University Giessen, Friedrichstrasse 24, 35392, Giessen, Germany
| | - Tilman Borggrefe
- Institute of Biochemistry, Justus-Liebig-University Giessen, Friedrichstrasse 24, 35392, Giessen, Germany.
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Gilardini Montani MS, Benedetti R, Cirone M. Targeting EZH2 in Cancer: Mechanisms, Pathways, and Therapeutic Potential. Molecules 2024; 29:5817. [PMID: 39769907 PMCID: PMC11678268 DOI: 10.3390/molecules29245817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Enhancer of zeste homolog 2 (EZH2) is a methyltransferase involved in cell cycle regulation, cell differentiation, and cell death and plays a role in modulating the immune response. Although it mainly functions by catalyzing the tri-methylation of H3 histone on K27 (H3K27), to inhibit the transcription of target genes, EZH2 can directly methylate several transcription factors or form complexes with them, regulating their functions. EZH2 expression/activity is often dysregulated in cancer, contributing to carcinogenesis and immune escape, thereby representing an important target in anti-cancer therapy. This review summarizes some of the mechanisms through which EZH2 regulates the expression and function of tumor suppressor genes and oncogenic molecules such as STAT3, mutant p53, and c-Myc and how it modulates the anti-cancer immune response. The influence of posttranslational modifications on EZH2 activity and stability and the possible strategies leading to its inhibition are also reviewed.
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Affiliation(s)
| | | | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
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Hoffman OR, Koehler JL, Espina JEC, Patterson AM, Gohar ES, Coleman E, Schoenike BA, Espinosa-Garcia C, Paredes F, Varvel NH, Dingledine RJ, Maguire JL, Roopra AS. Disease modification upon brief exposure to tofacitinib during chronic epilepsy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.08.07.552299. [PMID: 37662337 PMCID: PMC10473616 DOI: 10.1101/2023.08.07.552299] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
All current drug treatments for epilepsy, a neurological disorder affecting over 50 million people( 1, 2 ) merely treat symptoms, and a third of patients do not respond to medication. There are no disease modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits( 3, 4 ). Applying network approaches to rodent models and human temporal lobectomy samples at both whole tissue and single-nuclei resolutions, we observe the well-characterized pattern of rapid induction and subsequent quenching exhibited of the JAK/STAT pathway within days of epileptogenic insult. This is followed by a resurgent activation weeks to months later with the onset of spontaneous seizures. Targeting the first wave of activation after epileptic insult does not prevent disease. However, brief inhibition of the second wave with CP690550 (Tofacitinib) ( 5, 6 ) enduringly suppresses seizures, rescues deficits in spatial memory, and alleviates epilepsy-associated histopathological alterations. Seizure suppression lasts for at least 2 months after the final dose. Using discovery-based transcriptomic analysis across models of epilepsy and validation of putative mechanisms with human data, we demonstrate a powerful approach to identifying disease modifying targets; this may be useful for other neurological disorders. With this approach, we find that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a window for disease modification with the FDA-approved, orally available drug CP690550.
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Seneviratne JA, Ravindrarajah D, Carter DR, Zhai V, Lalwani A, Krishan S, Balachandran A, Ng E, Pandher R, Wong M, Nero TL, Wang S, Norris MD, Haber M, Liu T, Parker MW, Cheung BB, Marshall GM. Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma. Cancer Med 2024; 13:e70082. [PMID: 39501501 PMCID: PMC11538032 DOI: 10.1002/cam4.70082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/11/2024] [Accepted: 07/24/2024] [Indexed: 11/09/2024] Open
Abstract
BACKGROUND The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. METHODS We performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. RESULTS We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4-mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. CONCLUSION Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
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Affiliation(s)
- Janith A. Seneviratne
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Daenikka Ravindrarajah
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Daniel R. Carter
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Biomedical EngineeringUniversity of Technology SydneySydneyNew South WalesAustralia
| | - Vicki Zhai
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
| | - Amit Lalwani
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
| | - Sukriti Krishan
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Anushree Balachandran
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
| | - Ernest Ng
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Ruby Pandher
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Matthew Wong
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Tracy L. Nero
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteThe University of MelbourneParkvilleVictoriaAustralia
| | - Shudong Wang
- Centre for Drug Discovery and Development, Clinical and Health SciencesUniversity of South AustraliaAdelaideSouth AustraliaAustralia
| | - Murray D. Norris
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
- Centre for Childhood Cancer ResearchUNSW SydneyRandwickNew South WalesAustralia
| | - Michelle Haber
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Tao Liu
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Michael W. Parker
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteThe University of MelbourneParkvilleVictoriaAustralia
- ACRF Rational Drug Discovery CentreSt. Vincent's Institute of Medical ResearchFitzroyVictoriaAustralia
| | - Belamy B. Cheung
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
| | - Glenn M. Marshall
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research CentreUNSW SydneyKensingtonNew South WalesAustralia
- School of Clinical Medicine, Faculty of Medicine and HealthUNSW SydneyKensingtonNew South WalesAustralia
- Kids Cancer CentreSydney Children's HospitalRandwickNew South WalesAustralia
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Lv J, Lan B, Fu L, He C, Zhou W, Wang X, Zhou C, Mao Z, Chen Y, Mei C, Xue C. EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease. J Transl Med 2024; 22:979. [PMID: 39472935 PMCID: PMC11520870 DOI: 10.1186/s12967-024-05785-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/18/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent genetic disorder characterized by the formation of renal cysts leading to kidney failure. Despite known genetic underpinnings, the variability in disease progression suggests additional regulatory layers, including epigenetic modifications. METHODS We utilized various ADPKD models, including Pkd1 and Ezh2 conditional knockout (Pkd1delta/delta:Ezh2delta/delta) mice, to explore the role of Enhancer of Zeste Homolog 2 (EZH2) in cystogenesis. Pharmacological inhibition of EZH2 was performed using GSK126 or EPZ-6438 across multiple models. RESULTS EZH2 expression was significantly upregulated in Pkd1-/- cells, Pkd1delta/delta mice, and human ADPKD kidneys. EZH2 inhibition attenuates cyst development in MDCK cells and a mouse embryonic kidney cyst model. Both Ezh2 conditional knockout and GSK126 treatment suppressed renal cyst growth and protected renal function in Pkd1delta/delta mice. Mechanistically, cAMP/PKA/CREB pathway increased EZH2 expression. EZH2 mediated cystogenesis by enhancing methylation and activation of STAT3, promoting cell cycle through p21 suppression, and stimulating non-phosphorylated β-catenin in Wnt signaling pathway. Additionally, EZH2 enhanced ferroptosis by inhibiting SLC7A11 and GPX4 in ADPKD. CONCLUSION Our findings elucidate the pivotal role of EZH2 in promoting renal cyst growth through epigenetic mechanisms and suggest that EZH2 inhibition or ablation may serve as a novel therapeutic approach for managing ADPKD.
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Affiliation(s)
- Jiayi Lv
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China
| | - Bingxue Lan
- Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, China
- Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China
| | - Lili Fu
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China
| | - Chaoran He
- Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China
| | - Wei Zhou
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China
| | - Xi Wang
- Institute of Infectious Diseases, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
- Beijing Institute of Infectious Diseases, Beijing, 100015, China
| | - Chenchen Zhou
- Outpatient Department, Yangpu Third Military Retreat, Shanghai, China
| | - Zhiguo Mao
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China.
| | - Yupeng Chen
- Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China.
| | - Changlin Mei
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China.
| | - Cheng Xue
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China.
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Campolo M, Scuderi SA, Filippone A, Bova V, Lombardo SP, Colarossi L, Sava S, Capra AP, De Gaetano F, Portelli M, Militi A, Esposito E, Paterniti I. EZH2 Inhibition to Counteract Oral Cancer Progression through Wnt/β-Catenin Pathway Modulation. Pharmaceuticals (Basel) 2024; 17:1102. [PMID: 39204206 PMCID: PMC11357505 DOI: 10.3390/ph17081102] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common human malignancies worldwide. The molecular mechanisms of OSCC pathogenesis are still unknown; however, in recent years, several reports have focused on the role of enhancer of zeste homolog 2 (EZH2) in OSCC. Therefore, in this study we aimed to investigate the effects of GSK343, a selective EZH2 inhibitor, and its impact on the signaling pathways in OSCC, using an in vitro and in vivo orthotopic model. In the in vitro model, GSK343 (1, 10, and 25 μM) significantly decreased OSCC cell viability and cell migration through EZH2 inhibition, modulating NF-κB/IκBα pathway activation and eNOS, VEGF, and TGFβ expression, important markers of angiogenesis. In the in vivo model, GSK343 (5 mg/kg and 10 mg/kg) restored tongue tissue architecture and reduced tumor progression through EZH2 inhibition and Wnt/β-catenin signaling pathway modulation. Moreover, GSK343 reduced the expression of inflammatory mediators; eNOS and TGFβ, markers of angiogenesis; and CD31 and CD34, markers of micro vessel density, respectively. In conclusion, our data demonstrate that GSK343 counteracts oral cancer progression through EZH2/Wnt/β-catenin pathway modulation, suggesting that it could be a promising therapeutic approach for OSCC management.
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Affiliation(s)
- Michela Campolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
| | - Sarah Adriana Scuderi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
| | - Alessia Filippone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
| | - Valentina Bova
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
| | - Sofia Paola Lombardo
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, CT, Italy; (S.P.L.); (L.C.); (S.S.)
| | - Lorenzo Colarossi
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, CT, Italy; (S.P.L.); (L.C.); (S.S.)
| | - Serena Sava
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, CT, Italy; (S.P.L.); (L.C.); (S.S.)
| | - Anna Paola Capra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
| | - Federica De Gaetano
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
| | - Marco Portelli
- Department of Biomedical and Dental Science, Morphological and Functional Images, University of Messina, Via Consolare Valeria, 98125 Messina, ME, Italy; (M.P.); (A.M.)
| | - Angela Militi
- Department of Biomedical and Dental Science, Morphological and Functional Images, University of Messina, Via Consolare Valeria, 98125 Messina, ME, Italy; (M.P.); (A.M.)
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ME, Italy; (M.C.); (S.A.S.); (A.F.); (V.B.); (A.P.C.); (F.D.G.); (I.P.)
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10
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Karim A, Garg R, Saikia B, Tiwari A, Sahu S, Malhotra M, Minz RW, Rawat A, Singh S, Suri D. Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome. Front Immunol 2024; 15:1332817. [PMID: 39229272 PMCID: PMC11369709 DOI: 10.3389/fimmu.2024.1332817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 04/09/2024] [Indexed: 09/05/2024] Open
Abstract
Background Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. Objective This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. Methodology The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. Results A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. Conclusion The reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.
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Affiliation(s)
- Adil Karim
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rashi Garg
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Biman Saikia
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Abha Tiwari
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Smrity Sahu
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Mehak Malhotra
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ranjana W. Minz
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Surjit Singh
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepti Suri
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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11
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Wu J, Huang M, Dong W, Chen Y, Zhou Q, Zhang Q, Zheng J, Liu Y, Zhang Y, Liu S, Yang C, Chen S, Huang J, Lin T, Chen X. SUMO E3 ligase MUL1 inhibits lymph node metastasis of bladder cancer by mediating mitochondrial HSPA9 translocation. Int J Biol Sci 2024; 20:3986-4006. [PMID: 39113711 PMCID: PMC11302872 DOI: 10.7150/ijbs.98772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/09/2024] [Indexed: 08/10/2024] Open
Abstract
Lymph node (LN) metastasis is the dominant cause of death in bladder cancer (BCa) patients, but the underlying mechanism remains largely unknown. In recent years, accumulating studies have confirmed that bidirectional mitochondria-nucleus communication is essential for sustaining multiple function of mitochondria. However, little has been studied regarding whether and how the translocation of mitochondrial proteins is involved in LN metastasis. In this study, we first identified that the SUMO E3 ligase MUL1 was significantly downregulated in LN-metastatic BCa tissues and correlated with a good prognosis. Mechanistically, MUL1 SUMOylated HSPA9 at the K612 residue, leading to HSPA9 export from mitochondria and interaction with SUZ12 and in the nucleus. Consequently, MUL1 induced the ubiquitination-mediated degradation of SUZ12 and EZH2 and induced downstream STAT3 pathway inhibition in a HSPA9-dependent manner. Importantly, mutation of HSPA9 SUMO-conjugation motifs limited the translocation of mitochondrial HSPA9 and blocked the HSPA9-SUZ12 and HSPA9-EZH2 interactions. With mutation of the HSPA9 K612 site, the suppressive role of MUL1 overexpression was lost in BCa cells. Further in vitro and in vivo assays revealed that MUL1 inhibits the metastasis and proliferation of BCa cells. Overall, our study reveals a novel function and molecular mechanism of SUMO E3 ligases in LN metastasis.
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Affiliation(s)
- Jilin Wu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Ming Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Wen Dong
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
| | - Yuelong Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Qianghua Zhou
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Qiang Zhang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Junjiong Zheng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Yeqing Liu
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Yangjie Zhang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Sen Liu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Chenwei Yang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Siting Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Jian Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
| | - Tianxin Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
| | - Xu Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
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12
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Diallo M, Pimenta C, Murtinheira F, Martins-Alves D, Pinto FR, da Costa AA, Letra-Vilela R, Martin V, Rodriguez C, Rodrigues MS, Herrera F. Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor. Cell Oncol (Dordr) 2024; 47:1065-1070. [PMID: 38150153 PMCID: PMC11219437 DOI: 10.1007/s13402-023-00911-9] [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] [Accepted: 12/08/2023] [Indexed: 12/28/2023] Open
Abstract
STAT3 is a pleiotropic transcription factor overactivated in 70% of solid tumours. We have recently reported that inactivating mutations on residues susceptible to post-translational modifications (PTMs) in only one of the monomers (i.e. asymmetric) caused changes in the cellular distribution of STAT3 homodimers. Here, we used more controlled experimental conditions, i.e. without the interference of endogenous STAT3 (STAT3-/- HeLa cells) and in the presence of a defined cytokine stimulus (Leukemia Inhibitory Factor, LIF), to provide further evidence that asymmetric PTMs affect the nuclear translocation of STAT3 homodimers. Time-lapse microscopy for 20 min after LIF stimulation showed that S727 dephosphorylation (S727A) and K685 inactivation (K685R) slightly enhanced the nuclear translocation of STAT3 homodimers, while K49 inactivation (K49R) delayed STAT3 nuclear translocation. Our findings suggest that asymmetrically modified STAT3 homodimers could be a new level of STAT3 regulation and, therefore, a potential target for cancer therapy.
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Affiliation(s)
- Mickael Diallo
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
- MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Constança Pimenta
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Fernanda Murtinheira
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
- MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Daniela Martins-Alves
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Francisco R Pinto
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - André Abrantes da Costa
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Ricardo Letra-Vilela
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
- MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Vanesa Martin
- Departamento de Morfología y Biología Celular, Facultad de Medicina, University of Oviedo, c/Julian Claveria, Oviedo, 33006, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain
| | - Carmen Rodriguez
- Departamento de Morfología y Biología Celular, Facultad de Medicina, University of Oviedo, c/Julian Claveria, Oviedo, 33006, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain
| | - Mário S Rodrigues
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Federico Herrera
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal.
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13
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Blawski R, Vokshi BH, Guo X, Kittane S, Sallaku M, Chen W, Gjyzari M, Cheung T, Zhang Y, Simpkins C, Zhou W, Kulick A, Zhao P, Wei M, Shivashankar P, Prioleau T, Razavi P, Koche R, Rebecca VW, de Stanchina E, Castel P, Chan HM, Scaltriti M, Cocco E, Ji H, Luo M, Toska E. Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer. Cell Rep 2024; 43:114174. [PMID: 38700982 PMCID: PMC11265541 DOI: 10.1016/j.celrep.2024.114174] [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: 11/06/2023] [Revised: 03/26/2024] [Accepted: 04/16/2024] [Indexed: 05/05/2024] Open
Abstract
Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.
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Affiliation(s)
- Ryan Blawski
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
| | - Bujamin H Vokshi
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
| | - Xinyu Guo
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Srushti Kittane
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA
| | - Mirna Sallaku
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Wanlu Chen
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Martina Gjyzari
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
| | | | - Yuhan Zhang
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA
| | - Christopher Simpkins
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
| | - Weiqiang Zhou
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Amanda Kulick
- Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Peihua Zhao
- Department of Oncology, KU Leuven, 3000 Leuven, Belgium
| | - Meihan Wei
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Pranavkrishna Shivashankar
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA
| | - Tatiana Prioleau
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
| | - Pedram Razavi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Richard Koche
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Vito W Rebecca
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA
| | - Elisa de Stanchina
- Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Pau Castel
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | | | | | - Emiliano Cocco
- Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
| | - Hongkai Ji
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Minkui Luo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Eneda Toska
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
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14
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Di Crosta M, Arena A, Benedetti R, Gilardini Montani MS, Cirone M. 5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells. Curr Issues Mol Biol 2024; 46:2468-2479. [PMID: 38534772 DOI: 10.3390/cimb46030156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Epigenetic modifications, including aberrant DNA methylation occurring at the promoters of oncogenes and oncosuppressor genes and histone modifications, can contribute to carcinogenesis. Aberrant methylation mediated by histone methylatransferases, alongside histones, can affect methylation of proteins involved in the regulation of pro-survival pathways such as JAK/STAT and contribute to their activation. In this study, we used DNA or histone demethylating agents, 5-Azacytidine (5-AZA) or DS-3201 (valemetostat), respectively, to treat primary effusion lymphoma (PEL) cells, alone or in combination with AG490, a Signal transducer and activator of transcription 3 (STAT3) inhibitor. Cell viability was investigated by trypan blue assay and FACS analysis. The molecular changes induced by 5-AZA and/or AG490 treatments were investigated by Western blot analysis, while cytokine release by PEL cells treated by these drugs was evaluated by Luminex. Statistical analyses were performed with Graphpad Prism® software (version 9) and analyzed by Student's t test or a nonparametric one-way ANOVA test. The results obtained in this study suggest that 5-AZA upregulated molecules that inhibit STAT3 tyrosine phosphorylation, namely Suppressor of Cytokine Signaling 3 (SOCS3) and tyrosine-protein phosphatase non-receptor type (PTPN) 6/Src homology region 2 domain-containing phosphatase-1 (SHP-1), reducing STAT3 activation and downregulating several STAT3 pro-survival targets in PEL cells. As this lymphoma is highly dependent on the constitutive activation of STAT3, 5-AZA impaired PEL cell survival, and when used in combination with AG490 JAK2/STAT3 inhibitor, it potentiated its cytotoxic effect. Differently from 5-AZA, the inhibition of the EZH1/2 histone methyltransferase by DS-3201, reported to contribute to STAT3 activation in other cancers, slightly affected STAT3 phosphorylation or survival in PEL cells, either alone or in combination with AG490. This study suggests that 5-AZA, by upregulating the expression level of SOCS3 and PTPN6/SHP1, reduced STAT3 activation and improved the outcome of treatment targeting this transcription factor in PEL cells.
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Affiliation(s)
- Michele Di Crosta
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Andrea Arena
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Rossella Benedetti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | | | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
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15
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Hu Y, Dong Z, Liu K. Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery. J Exp Clin Cancer Res 2024; 43:23. [PMID: 38245798 PMCID: PMC10799433 DOI: 10.1186/s13046-024-02949-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/08/2024] [Indexed: 01/22/2024] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer.
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Affiliation(s)
- Yamei Hu
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
- Medical Research Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zigang Dong
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450008, Henan, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
| | - Kangdong Liu
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450008, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, Henan, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
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16
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Song D, Hu F, Huang C, Lan J, She X, Zhao C, Wu H, Liu A, Wu Q, Chen Y, Luo X, Feng Y, Yang X, Xu C, Hu J, Wang G. Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis. Proc Natl Acad Sci U S A 2023; 120:e2305684120. [PMID: 38113258 PMCID: PMC10756287 DOI: 10.1073/pnas.2305684120] [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: 04/15/2023] [Accepted: 10/03/2023] [Indexed: 12/21/2023] Open
Abstract
Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.
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Affiliation(s)
- Da Song
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Fuqing Hu
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Changsheng Huang
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Jingqin Lan
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Xiaowei She
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Chongchong Zhao
- Department of Protein Chemistry and Proteinomics Facility at Technology Center for Protein Sciences, Tsinghua University, Beijing100084, China
| | - Hong Wu
- Department of Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology, Chengdu610000, China
| | - Anyi Liu
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Qi Wu
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Yaqi Chen
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Xuelai Luo
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Yongdong Feng
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Xiangping Yang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan430030, China
| | - Chuan Xu
- Department of Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology, Chengdu610000, China
| | - Junbo Hu
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
| | - Guihua Wang
- Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan430030, China
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17
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Zimmerman SM, Lin PN, Souroullas GP. Non-canonical functions of EZH2 in cancer. Front Oncol 2023; 13:1233953. [PMID: 37664059 PMCID: PMC10473085 DOI: 10.3389/fonc.2023.1233953] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 07/21/2023] [Indexed: 09/05/2023] Open
Abstract
Mutations in chromatin modifying genes frequently occur in many kinds of cancer. Most mechanistic studies focus on their canonical functions, while therapeutic approaches target their enzymatic activity. Recent studies, however, demonstrate that non-canonical functions of chromatin modifiers may be equally important and therapeutically actionable in different types of cancer. One epigenetic regulator that demonstrates such a dual role in cancer is the histone methyltransferase EZH2. EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which plays a crucial role in cell identity, differentiation, proliferation, stemness and plasticity. While much of the regulatory functions and oncogenic activity of EZH2 have been attributed to its canonical, enzymatic activity of methylating lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark, recent studies suggest that non-canonical functions that are independent of H3K27me3 also contribute towards the oncogenic activity of EZH2. Contrary to PRC2's canonical repressive activity, mediated by H3K27me3, outside of the complex EZH2 can directly interact with transcription factors and oncogenes to activate gene expression. A more focused investigation into these non-canonical interactions of EZH2 and other epigenetic/chromatin regulators may uncover new and more effective therapeutic strategies. Here, we summarize major findings on the non-canonical functions of EZH2 and how they are related to different aspects of carcinogenesis.
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Affiliation(s)
- Sarah M. Zimmerman
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Phyo Nay Lin
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - George P. Souroullas
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Siteman Comprehensive Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
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18
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Abstract
The enhancer of zeste homolog 2 (EZH2) is encoded by the Enhancer of zeste 2 polycomb repressive complex 2 subunit gene. EZH2 is involved in the cell cycle, DNA damage repair, cell differentiation, autophagy, apoptosis, and immunological modulation. The main function of EZH2 is to catalyze the methylation of H3 histone of H3K27Me3, which inhibits the transcription of target genes, such as tumor suppressor genes. EZH2 also forms complexes with transcriptions factors or directly binds to the promoters of target genes, leading to regulate gene transcriptions. EZH2 has been as a prominent target for cancer therapy and a growing number of potential targeting medicines have been developed. This review summarized the mechanisms that EZH2 regulates gene transcription and the interactions between EZH2 and important intracellular signaling molecules (Wnt, Notch, MEK, Akt) and as well the clinical applications of EZH2-targeted drugs.
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Affiliation(s)
- Yuankai Liu
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China
| | - Qiong Yang
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China.
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19
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Arena A, Romeo MA, Benedetti R, Gilardini Montani MS, Santarelli R, Gonnella R, D'Orazi G, Cirone M. NRF2 and STAT3: friends or foes in carcinogenesis? Discov Oncol 2023; 14:37. [PMID: 37000324 PMCID: PMC10064365 DOI: 10.1007/s12672-023-00644-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/24/2023] [Indexed: 04/01/2023] Open
Abstract
NRF2 is a transcription factor that plays a pivotal role in carcinogenesis, also through the interaction with several pro-survival pathways. NRF2 controls the transcription of detoxification enzymes and a variety of other molecules impinging in several key biological processes. This perspective will focus on the complex interplay of NRF2 with STAT3, another transcription factor often aberrantly activated in cancer and driving tumorigenesis as well as immune suppression. Both NRF2 and STAT3 can be regulated by ER stress/UPR activation and their cross-talk influences and is influenced by autophagy and cytokines, contributing to shape the microenvironment, and both control the execution of DDR, also by regulating the expression of HSPs. Given the importance of these transcription factors, more investigations aimed at better elucidating the outcome of their networking could help to discover new and more efficacious strategies to fight cancer.
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Affiliation(s)
- Andrea Arena
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Maria Anele Romeo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Rossella Benedetti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | | | - Roberta Santarelli
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Roberta Gonnella
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Gabriella D'Orazi
- Department of Neurosciences, Imaging and Clinical Sciences, University "G. D'Annunzio", 66013, Chieti, Italy
- School of Medicine, UniCamillus International University, 00131, Rome, Italy
| | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
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20
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Zhao Y, Cheng Y, Qu Y. The role of EZH2 as a potential therapeutic target in retinoblastoma. Exp Eye Res 2023; 227:109389. [PMID: 36669714 DOI: 10.1016/j.exer.2023.109389] [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: 10/02/2022] [Revised: 01/03/2023] [Accepted: 01/15/2023] [Indexed: 01/20/2023]
Abstract
Enhancer of zeste homolog 2 (EZH2) has been reported selectively expressed in postnatal human retinoblastoma (RB). While, the contribution of EZH2 in progression of RB and its clinical importance has not been clarified. Here, immunohistochemistry (IHC) was performed on tumor specimens from 53 RB patients. UNC1999 and GSK503, inhibitors targeting EZH2, were incubated with human RB cell line WERI-Rb-1 and Y79 to assess the role and mechanism of EZH2 in RB proliferation, metastasis and tumor glycolysis. Administration of UNC1999 in subcutaneous tumor model of RB was conducted. The results showed that highly expressed EZH2 in RB tissues was significantly associated with the poor overall survival. UNC1999 and GSK503 inhibited proliferation, migration, invasion and tumor glycolysis of RB. Results in mouse xenograft model confirmed the inhibitory effect of UNC1999 on tumor growth of RB and the regulation effect of EZH2 to STAT3/FoxO1 signaling pathway. Therefore, EZH2 is rewarding to study as a potential target for anti-RB treatment.
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Affiliation(s)
- Yuqing Zhao
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China; Jinan Clinical Research Center for Geriatric Medicine, 202132001, China
| | - Ying Cheng
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China; Jinan Clinical Research Center for Geriatric Medicine, 202132001, China
| | - Yi Qu
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China; Jinan Clinical Research Center for Geriatric Medicine, 202132001, China.
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21
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Zimmerman SM, Nixon SJ, Chen PY, Raj L, Smith SR, Paolini RL, Lin PN, Souroullas GP. Ezh2 Y641F mutations co-operate with Stat3 to regulate MHC class I antigen processing and alter the tumor immune response in melanoma. Oncogene 2022; 41:4983-4993. [PMID: 36220978 PMCID: PMC9669177 DOI: 10.1038/s41388-022-02492-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 09/25/2022] [Accepted: 09/28/2022] [Indexed: 11/08/2022]
Abstract
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic component of the Polycomb Repressive Complex 2, a chromatin modifying complex, which mediates methylation of lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark. Genetic alterations in EZH2 in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641) whose underlying oncogenic mechanisms remain largely unknown. Here, we found that expression of Ezh2Y641F causes upregulation of a subset of interferon-regulated genes in melanoma cells. Upregulation of these genes was not a direct effect of changes in H3K27me3, but via a non-canonical interaction between Ezh2 and Signal Transducer and Activator of Transcription 3 (Stat3). Ezh2 and Stat3 together function as transcriptional activators to mediate gene activation of numerous genes, including MHC Class 1b antigen processing genes. Furthermore, expression of Stat3 is required to maintain an anti-tumor immune response in Ezh2Y641F melanomas and to prevent melanoma progression and recurrence.
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Affiliation(s)
- Sarah M Zimmerman
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Samantha J Nixon
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Pei Yu Chen
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Leela Raj
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Sofia R Smith
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Rachel L Paolini
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Phyo Nay Lin
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - George P Souroullas
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA.
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA.
- Siteman Comprehensive Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA.
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22
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Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis. Nat Immunol 2022; 23:1342-1354. [PMID: 35995859 DOI: 10.1038/s41590-022-01287-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 07/14/2022] [Indexed: 12/24/2022]
Abstract
Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.
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23
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STAT3 in medulloblastoma: a key transcriptional regulator and potential therapeutic target. Mol Biol Rep 2022; 49:10635-10652. [PMID: 35716286 DOI: 10.1007/s11033-022-07694-6] [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: 04/04/2022] [Accepted: 06/08/2022] [Indexed: 10/18/2022]
Abstract
Medulloblastoma is the most common malignant brain tumor of childhood accounting for about 60% of all pediatric embryonal tumors. Despite improvements in the overall survival rate, this tumor still lacks an efficient, reliable, and less toxic therapeutic approach. Characterization of the molecular mechanisms involved in medulloblastoma initiation and progression is a crucial step for the development of effective therapies. Signal transducer and activator of transcription 3 is a convergence point for several signaling cascades that are implicated in medulloblastoma tumorigenesis. Accumulated evidence has revealed the pivotal role of signal transducer and activator of transcription 3 in medulloblastoma pathogenesis such as proliferation, survival, angiogenesis, and immunosuppression as well as maintenance, drug resistance, and recurrence. In this review, we focus on the role of signal transducer and activator of transcription 3 in medulloblastoma tumorigenesis and discuss the recent advances of signal transducer and activator of transcription 3 inhibition as a promising developed strategy for medulloblastoma therapy.
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24
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Li C, Song J, Guo Z, Gong Y, Zhang T, Huang J, Cheng R, Yu X, Li Y, Chen L, Ma X, Sun Y, Wang Y, Xue L. EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment. Front Immunol 2022; 13:857808. [PMID: 35432300 PMCID: PMC9010515 DOI: 10.3389/fimmu.2022.857808] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/04/2022] [Indexed: 12/14/2022] Open
Abstract
EZH2 inhibitors (EZH2i), a class of small-molecule inhibitors that target EZH2 to exert anti-tumor functions, have just been approved by the US Food and Drug Administration (FDA) in treatment of adults and adolescents with locally advanced or metastatic epithelioid sarcoma. The application of EZH2i in several solid tumors is still in different stages of clinical trials and needs to be further validated. As a key epigenetic regulator, besides its role in controlling the proliferation of tumor cells, EZH2 has been implicated in the regulation of various immune cells including macrophages. But there are still controversial research results at present. Colorectal cancer (CRC) is a common malignant tumor that highly expresses EZH2, which has the third highest incidence and is the second leading cause of cancer-related death worldwide. Studies have shown that the numbers of M2-type tumor-associated macrophages (TAMs) are highly associated with the progression and metastasis of CRC. In the current study, we aim to investigate how EZH2 modulates the polarization of macrophages in the tumor microenvironment (TME) of CRC, and compare the role of two different EZH2 inhibitors, EPZ6438 and GSK126. We applied a 3D culture method to demonstrate that EZH2i did indeed suppress the proliferation of CRC cells in vitro. In vivo, we found that the percentage of CD206+ macrophages of the TME was decreased under the treatment of EPZ6438, but it increased upon GSK126 treatment. Besides, in the co-culture system of macrophages and CRC cells, EPZ6438 led to significant elevation of M1 markers and reduction of M2 markers. Furthermore, mechanistic studies validated by ChIP-qPCR demonstrated that EZH2i inhibit EZH2-mediated H3K27me3 levels on the promoters of STAT3, an essential transcription factor for M1 macrophage polarization. Therefore, our data suggested that EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect. Moreover, our study provided new insight for better understanding of the role of two kinds of EZH2i: EPZ6438 and GSK126, which may pave the way in treating CRC by targeting cancer cells and immune cells via this epigenetic approach in the future.
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Affiliation(s)
- Chen Li
- Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Jiagui Song
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Zhengyang Guo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Yueqing Gong
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Tengrui Zhang
- Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Jiaqi Huang
- Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Rui Cheng
- Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Xiaotong Yu
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Yanfang Li
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Li Chen
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Xiaojuan Ma
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Yan Sun
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Yan Wang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- *Correspondence: Lixiang Xue, ; Yan Wang,
| | - Lixiang Xue
- Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- *Correspondence: Lixiang Xue, ; Yan Wang,
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25
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Thulabandu V, Ferguson JW, Phung M, Atit RP. EZH2 modulates retinoic acid signaling to ensure myotube formation during development. FEBS Lett 2022; 596:1672-1685. [PMID: 35294045 DOI: 10.1002/1873-3468.14334] [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: 07/26/2021] [Revised: 02/27/2022] [Accepted: 03/02/2022] [Indexed: 11/09/2022]
Abstract
Sequential differentiation of pre-somitic progenitors into myocytes and subsequently into myotubes and myofibers is essential for the myogenic differentiation program (MDP) crucial for muscle development. Signaling factors involved in MDP are Polycomb Repressive Complex 2 (PRC2) targets in various developmental contexts. PRC2 is active in the developing myotomes during MDP, but how it regulates MDP is unclear. Here, we found that myocyte differentiation to myotubes requires Enhancer of Zeste 2 (EZH2), the catalytic component of PRC2. We observed elevated retinoic-acid (RA) signaling in the prospective myocytes in the Ezh2 mutants (E8.5-MusEzh2 ), and its inhibition can partially rescue the myocyte differentiation defect. Together, our data demonstrate a new role for PRC2-EZH2 during myocyte differentiation into myotubes by modulating RA signaling.
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Affiliation(s)
- Venkata Thulabandu
- Dept. of Biology, Case Western Reserve University, Cleveland, Ohio, U.S.A
| | - James W Ferguson
- Dept. of Biology, Case Western Reserve University, Cleveland, Ohio, U.S.A
| | - Melissa Phung
- Dept. of Biology, Case Western Reserve University, Cleveland, Ohio, U.S.A
| | - Radhika P Atit
- Dept. of Biology, Case Western Reserve University, Cleveland, Ohio, U.S.A.,Dept. of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, U.S.A.,Dept. of Dermatology, Case Western Reserve University, Cleveland, Ohio, U.S.A
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26
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STAT3 Role in T-Cell Memory Formation. Int J Mol Sci 2022; 23:ijms23052878. [PMID: 35270020 PMCID: PMC8910982 DOI: 10.3390/ijms23052878] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/12/2022] Open
Abstract
Along with the clinical success of immuno-oncology drugs and cellular therapies, T-cell biology has attracted considerable attention in the immunology community. Long-term immunity, traditionally analyzed in the context of infection, is increasingly studied in cancer. Many signaling pathways, transcription factors, and metabolic regulators have been shown to participate in the formation of memory T cells. There is increasing evidence that the signal transducer and activator of transcription-3 (STAT3) signaling pathway is crucial for the formation of long-term T-cell immunity capable of efficient recall responses. In this review, we summarize what is currently known about STAT3 role in the context of memory T-cell formation and antitumor immunity.
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27
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Dolatabadi S, Jonasson E, Andersson L, Luna Santamaría M, Lindén M, Österlund T, Åman P, Ståhlberg A. FUS-DDIT3 Fusion Oncoprotein Expression Affects JAK-STAT Signaling in Myxoid Liposarcoma. Front Oncol 2022; 12:816894. [PMID: 35186752 PMCID: PMC8851354 DOI: 10.3389/fonc.2022.816894] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/06/2022] [Indexed: 11/25/2022] Open
Abstract
Myxoid liposarcoma is one of the most common sarcoma entities characterized by FET fusion oncogenes. Despite a generally favorable prognosis of myxoid liposarcoma, chemotherapy resistance remains a clinical problem. This cancer stem cell property is associated with JAK-STAT signaling, but the link to the myxoid-liposarcoma-specific FET fusion oncogene FUS-DDIT3 is not known. Here, we show that ectopic expression of FUS-DDIT3 resulted in elevated levels of STAT3 and phosphorylated STAT3. RNA sequencing identified 126 genes that were regulated by both FUS-DDIT3 expression and JAK1/2 inhibition using ruxolitinib. Sixty-six of these genes were connected in a protein interaction network. Fifty-three and 29 of these genes were confirmed as FUS-DDIT3 and STAT3 targets, respectively, using public chromatin immunoprecipitation sequencing data sets. Enriched gene sets among the 126 regulated genes included processes related to cytokine signaling, adipocytokine signaling, and chromatin remodeling. We validated CD44 as a target gene of JAK1/2 inhibition and as a potential cancer stem cell marker in myxoid liposarcoma. Finally, we showed that FUS-DDIT3 interacted with phosphorylated STAT3 in association with subunits of the SWI/SNF chromatin remodeling complex and PRC2 repressive complex. Our data show that the function of FUS-DDIT3 is closely connected to JAK-STAT signaling. Detailed deciphering of molecular mechanisms behind tumor progression opens up new avenues for targeted therapies in sarcomas and leukemia characterized by FET fusion oncogenes.
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Affiliation(s)
- Soheila Dolatabadi
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Emma Jonasson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Lisa Andersson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Manuel Luna Santamaría
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Malin Lindén
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Tobias Österlund
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Pierre Åman
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anders Ståhlberg
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
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28
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Shih PC. The role of the STAT3 signaling transduction pathways in radioresistance. Pharmacol Ther 2022; 234:108118. [PMID: 35085605 DOI: 10.1016/j.pharmthera.2022.108118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/25/2021] [Accepted: 01/18/2022] [Indexed: 12/11/2022]
Abstract
The efficacy of radiotherapy has long known to be limited by the emergence of resistance. The four Rs of radiotherapy (DNA damage repair, reoxygenation, redistribution of the cell cycle, and repopulation) are generally accepted concepts in radiobioolgy. Recent studies have strongly linked signal transducer and activator of transcription 3 (STAT3) to the regulation of cancer stemness and radioresistance. In particular, a STAT3 pathway inhibitor napabucasin, claimed to be the first cancer stemness antagonist in clinical trials, strengthens the link. However, no reviews connect STAT3 with the four Rs of radiotherapy. Herein, the evidence-based role of STAT3 in radioresistance is discussed in relation to the four Rs of radiotherapy. The proposed mechanisms include upstream and downstream effector proteins of STAT3, including FOXM1, MELK, NEK2, AKT, EZH2, and HIF1α. Downstream transcriptional products of the mechanistically-related proteins are involved in cancer stemness, anti-apoptosis, and the four Rs of radiotherapy. Utilizing selective inhibitors of the mechanistically-related proteins has shown promising antagonism of radioresistance, suggesting that the expression levels of these proteins may be biomarkers for the prediction of radiotherapeutic outcomes, and that this molecular mechanism may provide a rational axis through which to treat radioresistance.
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Affiliation(s)
- Po-Chang Shih
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, Bloomsbury, London WC1N 1AX, UK; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
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29
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Huang C, Hu F, Song D, Sun X, Liu A, Wu Q, She X, Chen Y, Chen L, Hu F, Xu F, Luo X, Feng Y, Yang X, Hu J, Wang G. Smad3 methylation by EZH2 promotes its activation and tumor metastasis. J Clin Invest 2022; 132:152394. [PMID: 35085106 PMCID: PMC8884901 DOI: 10.1172/jci152394] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 01/11/2022] [Indexed: 11/17/2022] Open
Abstract
SMAD3 plays a central role in cancer metastasis, and its hyperactivation is linked to poor cancer outcomes. Thus, it is critical to understand the upstream signaling pathways that govern SMAD3 activation. Here, we report that SMAD3 underwent methylation at K53 and K333 (K53/K333) by EZH2, a process crucial for cell membrane recruitment, phosphorylation, and activation of SMAD3 upon TGFB1 stimulation. Mechanistically, EZH2-triggered SMAD3 methylation facilitated SMAD3 interaction with its cellular membrane localization molecule (SARA), which in turn sustained SMAD3 phosphorylation by the TGFB receptor. Pathologically, increased expression of EZH2 expression resulted in the accumulation of SMAD3 methylation to facilitate SMAD3 activation. EZH2-mediated SMAD3 K53/K333 methylation was upregulated and correlated with SMAD3 hyperactivation in breast cancer, promoted tumor metastasis, and was predictive of poor survival outcomes. We used 2 TAT peptides to abrogate SMAD3 methylation and therapeutically inhibit cancer metastasis. Collectively, these findings reveal the complicated layers involved in the regulation of SMAD3 activation coordinated by EZH2-mediated SMAD3 K53/K333 methylation to drive cancer metastasis.
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Affiliation(s)
- Changsheng Huang
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Fuqing Hu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Da Song
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xuling Sun
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Anyi Liu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Wu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaowei She
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yaqi Chen
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Lisheng Chen
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Fayong Hu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Xu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xuelai Luo
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yongdong Feng
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangping Yang
- Department of Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Junbo Hu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Guihua Wang
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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30
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Kim D, Park G, Huuhtanen J, Ghimire B, Rajala H, Moriggl R, Chan WC, Kankainen M, Myllymäki M, Mustjoki S. STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation. Leukemia 2021; 35:3430-3443. [PMID: 34075200 PMCID: PMC8632689 DOI: 10.1038/s41375-021-01296-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/04/2021] [Accepted: 05/05/2021] [Indexed: 12/20/2022]
Abstract
Large granular lymphocyte leukemia (LGLL) is characterized by somatic gain-of-function STAT3 mutations. However, the functional effects of STAT3 mutations on primary LGLL cells have not been studied in detail. In this study, we show that CD8+ T cells isolated from STAT3 mutated LGLL patients have high protein levels of epigenetic regulators, such as DNMT1, and are characterized by global hypermethylation. Correspondingly, treatment of healthy CD8+ T cells with IL-6, IL-15, and/or MCP-1 cytokines resulted in STAT3 activation, increased DNMT1, EZH2, c-MYC, l-MYC, MAX, and NFκB levels, increased DNA methylation, and increased oxidative stress. Similar results were discovered in KAI3 NK cells overexpressing gain-of-function STAT3Y640F and STAT3G618R mutants compared to KAI3 NK cells overexpressing STAT3WT. Our results also confirm that STAT3 forms a direct complex with DNMT1, EZH2, and HDAC1. In STAT3 mutated LGLL cells, DNA methyltransferase (DNMT) inhibitor azacitidine abrogated the activation of STAT3 via restored SHP1 expression. In conclusion, STAT3 mutations cause DNA hypermethylation resulting in sensitivity to DNMT inhibitors, which could be considered as a novel treatment option for LGLL patients with resistance to standard treatments.
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Affiliation(s)
- Daehong Kim
- Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
| | - Giljun Park
- Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
| | - Jani Huuhtanen
- Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
| | - Bishwa Ghimire
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Hanna Rajala
- Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
| | - Richard Moriggl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Wing C Chan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA
| | - Matti Kankainen
- Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Department of Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
| | - Mikko Myllymäki
- Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
| | - Satu Mustjoki
- Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
- Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
- iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
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31
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Tesoriere A, Dinarello A, Argenton F. The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions. Biomedicines 2021; 9:956. [PMID: 34440160 PMCID: PMC8393524 DOI: 10.3390/biomedicines9080956] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023] Open
Abstract
STAT3 is an important transcription factor that regulates cell growth and proliferation by regulating gene transcription of a plethora of genes. This protein also has many roles in cancer progression and several tumors such as prostate, lung, breast, and intestine cancers that are characterized by strong STAT3-dependent transcriptional activity. This protein is post-translationally modified in different ways according to cellular context and stimulus, and the same post-translational modification can have opposite effects in different cellular models. In this review, we describe the studies performed on the main modifications affecting the activity of STAT3: phosphorylation of tyrosine 705 and serine 727; acetylation of lysine 49, 87, 601, 615, 631, 685, 707, and 709; and methylation of lysine 49, 140, and 180. The extensive results obtained by different studies demonstrate that post-translational modifications drastically change STAT3 activities and that we need further analysis to properly elucidate all the functions of this multifaceted transcription factor.
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Affiliation(s)
| | | | - Francesco Argenton
- Dipartimento di Biologia, Università degli Studi di Padova, 35131 Padova, Italy; (A.T.); (A.D.)
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32
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Diallo M, Herrera F. The role of understudied post-translational modifications for the behavior and function of Signal Transducer and Activator of Transcription 3. FEBS J 2021; 289:6235-6255. [PMID: 34235865 DOI: 10.1111/febs.16116] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 12/19/2022]
Abstract
The Signal Transducer and Activator of Transcription (STAT) family of transcription factors is involved in inflammation, immunity, development, cancer, and response to injury, among other biological phenomena. Canonical STAT signaling is often represented as a 3-step pathway involving the sequential activation of a membrane receptor, an intermediate kinase, and a STAT transcription factor. The rate-limiting phosphorylation at a highly conserved C-terminal tyrosine residue determines the nuclear translocation and transcriptional activity of STATs. This apparent simplicity is actually misleading and can hardly explain the pleiotropic nature of STATs, the existence of various noncanonical STAT pathways, or the key role of the N-terminal domain in STAT functions. More than 80 post-translational modifications (PTMs) have been identified for STAT3, but their functions remain barely understood. Here, we provide a brief but comprehensive overview of these underexplored PTMs and their role on STAT3 canonical and noncanonical functions. A less tyrosine-centric point of view may be required to advance our understanding of STAT signaling.
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Affiliation(s)
- Mickael Diallo
- Faculdade de Ciências da Universidade de Lisboa, Cell Structure and Dynamics Laboratory, BioISI - Instituto de Biosistemas e Ciências integrativas, Lisbon, Portugal.,MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Federico Herrera
- Faculdade de Ciências da Universidade de Lisboa, Cell Structure and Dynamics Laboratory, BioISI - Instituto de Biosistemas e Ciências integrativas, Lisbon, Portugal.,MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
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33
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Greenfield G, McMullin MF, Mills K. Molecular pathogenesis of the myeloproliferative neoplasms. J Hematol Oncol 2021; 14:103. [PMID: 34193229 PMCID: PMC8246678 DOI: 10.1186/s13045-021-01116-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Despite distinct clinical entities, these disorders are linked by morphological similarities and propensity to thrombotic complications and leukaemic transformation. Current therapeutic options are limited in disease-modifying activity with a focus on the prevention of thrombus formation. Constitutive activation of the JAK/STAT signalling pathway is a hallmark of pathogenesis across the disease spectrum with driving mutations in JAK2, CALR and MPL identified in the majority of patients. Co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control and splicing of RNA are variably but recurrently identified across the MPN disease spectrum, whilst epigenetic contributors to disease are increasingly recognised. The prognostic implications of one MPN diagnosis may significantly limit life expectancy, whilst another may have limited impact depending on the disease phenotype, genotype and other external factors. The genetic and clinical similarities and differences in these disorders have provided a unique opportunity to understand the relative contributions to MPN, myeloid and cancer biology generally from specific genetic and epigenetic changes. This review provides a comprehensive overview of the molecular pathophysiology of MPN exploring the role of driver mutations, co-occurring mutations, dysregulation of intrinsic cell signalling, epigenetic regulation and genetic predisposing factors highlighting important areas for future consideration.
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Affiliation(s)
- Graeme Greenfield
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
| | | | - Ken Mills
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
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34
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Myristoylation-mediated phase separation of EZH2 compartmentalizes STAT3 to promote lung cancer growth. Cancer Lett 2021; 516:84-98. [PMID: 34102285 DOI: 10.1016/j.canlet.2021.05.035] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 01/27/2023]
Abstract
N-myristoylation is a crucial signaling and pathogenic modification process that confers hydrophobicity to cytosolic proteins. Although different large-scale approaches have been applied, a large proportion of myristoylated proteins remain to be identified. EZH2 is overexpressed in lung cancer cells and exerts oncogenic effects via its intrinsic methyltransferase activity. Using a well-established click chemistry approach, we found that EZH2 can be modified by myristoylation at its N-terminal glycine in lung cancer cells. Hydrophobic interaction is one of the main forces driving or stabilizing liquid-liquid phase separation (LLPS), raising the possibility that myristoylation can modulate LLPS by mediating hydrophobic interactions. Indeed, myristoylation facilitates EZH2 to form phase-separated liquid droplets in lung cancer cells and in vitro. Furthermore, we provide evidence that myristoylation-mediated LLPS of EZH2 compartmentalizes its non-canonical substrate, STAT3, and activates STAT3 signaling, ultimately resulting in accelerated lung cancer cell growth. Thus, targeting EZH2 myristoylation may have significant therapeutic efficacy in the treatment of lung cancer. Altogether, these observations not only extend the list of myristoylated proteins, but also indicate that hydrophobic lipidation may serve as a novel incentive to induce or maintain LLPS.
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35
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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability. Cell Death Dis 2021; 12:463. [PMID: 33966039 PMCID: PMC8106682 DOI: 10.1038/s41419-021-03734-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 04/07/2021] [Accepted: 04/07/2021] [Indexed: 01/12/2023]
Abstract
Resistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.
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36
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Anwar T, Gonzalez ME, Kleer CG. Noncanonical Functions of the Polycomb Group Protein EZH2 in Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:774-783. [PMID: 33556366 PMCID: PMC8127103 DOI: 10.1016/j.ajpath.2021.01.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/19/2021] [Indexed: 12/23/2022]
Abstract
Enhancer of Zeste Homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that is critical for determining cell identity. An epigenetic writer, EZH2 has a well-defined role in transcriptional repression by depositing trimethyl marks on lysine 27 of histone H3. However, there is mounting evidence that histone methyltransferases like EZH2 exert histone methyltransferase-independent functions. The relevance of these functions to breast cancer progression and their regulatory mechanisms are only beginning to become understood. Here, we review the current understanding of EZH2 H3K27me3-independent, noncanonical, functions and their regulation in breast cancer.
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Affiliation(s)
- Talha Anwar
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Maria E Gonzalez
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Celina G Kleer
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
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37
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NSD2 promotes tumor angiogenesis through methylating and activating STAT3 protein. Oncogene 2021; 40:2952-2967. [PMID: 33742125 DOI: 10.1038/s41388-021-01747-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/23/2021] [Accepted: 03/03/2021] [Indexed: 01/31/2023]
Abstract
Tumor angiogenesis plays vital roles in tumorigenesis and development; regulatory mechanism of angiogenesis is still not been fully elucidated. NSD2, a histone methyltransferase catalyzing di-methylation of histone H3 at lysine 36, has been proved a critical molecule in proliferation, metastasis, and tumorigenesis. But its role in tumor angiogenesis remains unknown. Here we demonstrated that NSD2 promoted tumor angiogenesis in vitro and in vivo. Furthermore, we confirmed that the angiogenic function of NSD2 was mediated by STAT3. Momentously, we found that NSD2 promoted the methylation and activation of STAT3. In addition, mass spectrometry and site-directed mutagenesis assays revealed that NSD2 methylated STAT3 at lysine 163 (K163). Meanwhile, K to R mutant at K163 of STAT3 attenuated the activation and angiogenic function of STAT3. Taken together, we conclude that methylation of STAT3 catalyzed by NSD2 promotes the activation of STAT3 pathway and enhances the ability of tumor angiogenesis. Our findings investigate a NSD2-dependent methylation-phosphorylation regulation pattern of STAT3 and reveal that NSD2/STAT3/VEGFA axis might be a potential target for tumor therapy.
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38
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Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach. Int J Mol Sci 2021; 22:ijms22062957. [PMID: 33803922 PMCID: PMC7999120 DOI: 10.3390/ijms22062957] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/11/2021] [Accepted: 03/12/2021] [Indexed: 12/13/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by a sustained elevation of pulmonary artery (PA) pressure, right ventricular failure, and premature death. Enhanced proliferation and resistance to apoptosis (as seen in cancer cells) of PA smooth muscle cells (PASMCs) is a major pathological hallmark contributing to pulmonary vascular remodeling in PAH, for which current therapies have only limited effects. Emerging evidence points toward a critical role for Enhancer of Zeste Homolog 2 (EZH2) in cancer cell proliferation and survival. However, its role in PAH remains largely unknown. The aim of this study was to determine whether EZH2 represents a new factor critically involved in the abnormal phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell-cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and tricarboxylic acid cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.
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39
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Zhang XN, Wu LJ, Kong X, Zheng BY, Zhang Z, He ZW. Regulation of the expression of proinflammatory cytokines induced by SARS-CoV-2. World J Clin Cases 2021; 9:1513-1523. [PMID: 33728295 PMCID: PMC7942047 DOI: 10.12998/wjcc.v9.i7.1513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/08/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023] Open
Abstract
An outbreak of a novel coronavirus was reported in Wuhan, China, in late 2019. It has spread rapidly through China and many other countries, causing a global pandemic. Since February 2020, over 28 countries/regions have reported confirmed cases. Individuals with the infection known as coronavirus disease-19 (COVID-19) have similar clinical features as severe acute respiratory syndrome first encountered 17 years ago, with fever, cough, and upper airway congestion, along with high production of proinflammatory cytokines (PICs), which form a cytokine storm. PICs induced by COVID-19 include interleukin (IL)-6, IL-17, and monocyte chemoattractant protein-1. The production of cytokines is regulated by activated nuclear factor-kB and involves downstream pathways such as Janus kinase/signal transducers and activators transcription. Protein expression is also regulated by post-translational modification of chromosomal markers. Lysine residues in the peptide tails stretching out from the core of histones bind the sequence upstream of the coding portion of genomic DNA. Covalent modification, particularly methylation, activates or represses gene transcription. PICs have been reported to be induced by histone modification and stimulate exudation of hyaluronic acid, which is implicated in the occurrence of COVID-19. These findings indicate the impact of the expression of PICs on the pathogenesis and therapeutic targeting of COVID-19.
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Affiliation(s)
- Xiang-Ning Zhang
- Department of Pathophysiology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Long-Ji Wu
- Department of Pathophysiology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Xia Kong
- Department of Pathophysiology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Bi-Ying Zheng
- Department of Clinical Microbiology, Institute of Laboratory Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Zhe Zhang
- Department of ENT and Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 531000, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Wei He
- Department of Pathophysiology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
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40
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Müller A, Dickmanns A, Resch C, Schäkel K, Hailfinger S, Dobbelstein M, Schulze-Osthoff K, Kramer D. The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis. J Clin Invest 2021; 130:5765-5781. [PMID: 32701505 DOI: 10.1172/jci134217] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
Psoriasis is a frequent, inflammatory skin disease characterized by keratinocyte hyperproliferation and a disease-related infiltration of immune cells. Here, we identified a novel proinflammatory signaling pathway driven by cyclin-dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid target for psoriasis therapy. Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby triggering a methylation-induced activation of STAT3. Subsequently, active STAT3 resulted in the induction of IκBζ, which is a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis-related proinflammatory gene expression by suppressing IκBζ induction in keratinocytes. Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to fully prevent the development of psoriasis in various mouse models by suppressing STAT3-mediated IκBζ expression. Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin lesions. Thus, this study not only identifies a novel psoriasis-relevant proinflammatory pathway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option for patients with psoriasis.
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Affiliation(s)
- Anne Müller
- Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany
| | - Antje Dickmanns
- Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University of Göttingen, Göttingen, Germany
| | - Claudia Resch
- Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany
| | - Knut Schäkel
- Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stephan Hailfinger
- Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180), Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany
| | - Matthias Dobbelstein
- Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University of Göttingen, Göttingen, Germany
| | - Klaus Schulze-Osthoff
- Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniela Kramer
- Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany
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41
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Lukinović V, Casanova AG, Roth GS, Chuffart F, Reynoird N. Lysine Methyltransferases Signaling: Histones are Just the Tip of the Iceberg. Curr Protein Pept Sci 2021; 21:655-674. [PMID: 31894745 DOI: 10.2174/1871527319666200102101608] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/15/2019] [Accepted: 11/27/2019] [Indexed: 12/28/2022]
Abstract
Protein lysine methylation is a functionally diverse post-translational modification involved in various major cellular processes. Lysine methylation can modulate proteins activity, stability, localization, and/or interaction, resulting in specific downstream signaling and biological outcomes. Lysine methylation is a dynamic and fine-tuned process, deregulation of which often leads to human pathologies. In particular, the lysine methylome and its associated signaling network can be linked to carcinogenesis and cancer progression. Histone modifications and chromatin regulation is a major aspect of lysine methylation importance, but increasing evidence suggests that a high relevance and impact of non-histone lysine methylation signaling has emerged in recent years. In this review, we draw an updated picture of the current scientific knowledge regarding non-histone lysine methylation signaling and its implication in physiological and pathological processes. We aim to demonstrate the significance of lysine methylation as a major and yet underestimated posttranslational modification, and to raise the importance of this modification in both epigenetic and cellular signaling by focusing on the observed activities of SET- and 7β-strandcontaining human lysine methyltransferases. Recent evidence suggests that what has been observed so far regarding lysine methylation's implication in human pathologies is only the tip of the iceberg. Therefore, the exploration of the "methylome network" raises the possibility to use these enzymes and their substrates as promising new therapeutic targets for the development of future epigenetic and methyllysine signaling cancer treatments.
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Affiliation(s)
- Valentina Lukinović
- Institute for Advanced Biosciences, INSERM U1209 - CNRS UMR5309 - Universite Grenoble Alpes, Grenoble Cedex, France
| | - Alexandre G Casanova
- Institute for Advanced Biosciences, INSERM U1209 - CNRS UMR5309 - Universite Grenoble Alpes, Grenoble Cedex, France
| | - Gael S Roth
- Institute for Advanced Biosciences, INSERM U1209 - CNRS UMR5309 - Universite Grenoble Alpes, Grenoble Cedex, France
| | - Florent Chuffart
- Institute for Advanced Biosciences, INSERM U1209 - CNRS UMR5309 - Universite Grenoble Alpes, Grenoble Cedex, France
| | - Nicolas Reynoird
- Institute for Advanced Biosciences, INSERM U1209 - CNRS UMR5309 - Universite Grenoble Alpes, Grenoble Cedex, France
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42
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Wang Y, Zhu L, Guo M, Sun G, Zhou K, Pang W, Cao D, Tang X, Meng X. Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2. Cell Death Discov 2021; 7:19. [PMID: 33469000 PMCID: PMC7815777 DOI: 10.1038/s41420-021-00402-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/02/2020] [Accepted: 12/23/2020] [Indexed: 12/25/2022] Open
Abstract
WHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in OS patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What's more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.
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Affiliation(s)
- Yu Wang
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Liming Zhu
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mei Guo
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Gang Sun
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Kun Zhou
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wenjing Pang
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dachun Cao
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Xin Tang
- Departments of Geriatrics, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Xiangjun Meng
- Departments of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Tolomeo M, Cascio A. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Int J Mol Sci 2021; 22:ijms22020603. [PMID: 33435349 PMCID: PMC7826746 DOI: 10.3390/ijms22020603] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/24/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.
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Han T, Zhuo M, Yuan C, Xiao X, Cui J, Qin G, Wang L, Jiao F. Coordinated silencing of the Sp1-mediated long noncoding RNA MEG3 by EZH2 and HDAC3 as a prognostic factor in pancreatic ductal adenocarcinoma. Cancer Biol Med 2020; 17:953-969. [PMID: 33299646 PMCID: PMC7721101 DOI: 10.20892/j.issn.2095-3941.2019.0427] [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: 11/27/2019] [Accepted: 07/10/2020] [Indexed: 12/14/2022] Open
Abstract
Objective: Pancreatic ductal adenocarcinoma (PDAC) is a disease with high mortality. Many so-called “junk” noncoding RNAs need to be discovered in PDAC. The purpose of this study was therefore to investigate the function and regulatory mechanism of the long noncoding RNA MEG3 in PDAC. Methods: The Gene Expression Omnibus database (GEO database) was used to determine the differential expression of long noncoding RNAs in PDAC, and MEG3 was selected for subsequent verification. Tissue and cell samples were used to verify MEG3 expression, followed by functional detection in vitro and in vivo. Microarrays were used to characterize long noncoding RNA and mRNA expression profiles. Competing endogenous RNA analyses were used to detect differential MEG3 and relational miRNA expression in PDAC. Finally, promoter analyses were conducted to explain the downregulation of MEG3 PDAC. Results: We generated a catalogue of PDAC-associated long noncoding RNAs in the GEO database. The ectopic expression of MEG3 inhibited PDAC growth and metastasis in vitro and in vivo, which was statistically significant (P < 0.05). Microarray analysis showed that multiple microRNAs interacted with MEG3. We also showed that MEG3, as a competing endogenous RNA, directly sponged miR-374a-5p to regulate PTEN expression. The transcription factor, Sp1, recruited EZH2 and HDAC3 to the promoter and transcriptionally repressed MEG3 expression. Finally, clinical data showed that MEG3 and miR-374a-5p expressions were correlated with clinicopathological features. Statistically, Sp1, EZH2, HDAC3, and miR-374a-5p were negatively correlated with MEG3 (P < 0.05). Conclusions: Reduced MEG3 levels played a crucial role in the PDAC malignant phenotype, which provided insight into novel and effective molecular targets of MEG3 for pancreatic cancer treatment.
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Affiliation(s)
- Ting Han
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Meng Zhuo
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Cuncun Yuan
- Department of Pathology, Fudan University Eye Ear Nose and Throat Hospital, Shanghai 201114, China
| | - Xiuying Xiao
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Jiujie Cui
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Guangrong Qin
- Shanghai Center for Bioinformation Technology, Shanghai 201203, China
| | - Liwei Wang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Feng Jiao
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
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45
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No Easy Way Out for EZH2: Its Pleiotropic, Noncanonical Effects on Gene Regulation and Cellular Function. Int J Mol Sci 2020; 21:ijms21249501. [PMID: 33327550 PMCID: PMC7765048 DOI: 10.3390/ijms21249501] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/14/2022] Open
Abstract
Enhancer of zeste homolog 2 (EZH2) plays critical roles in a range of biological processes including organ development and homeostasis, epigenomic and transcriptomic regulation, gene repression and imprinting, and DNA damage repair. A widely known function of EZH2 is to serve as an enzymatic subunit of Polycomb repressive complex 2 (PRC2) and catalyze trimethylation of histone H3 lysine 27 (H3K27me3) for repressing target gene expression. However, an increasing body of evidence demonstrates that EZH2 has many "non-conventional" functions that go beyond H3K27 methylation as a Polycomb factor. First, EZH2 can methylate a number of nonhistone proteins, thereby regulating cellular processes in an H3K27me3-independent fashion. Furthermore, EZH2 relies on both methyltransferase-dependent and methyltransferase-independent mechanisms for modulating gene-expression programs and/or epigenomic patterns of cells. Importantly, independent of PRC2, EZH2 also forms physical interactions with a number of DNA-binding factors and transcriptional coactivators to context-dependently influence gene expression. The purpose of this review is to detail the complex, noncanonical roles of EZH2, which are generally less appreciated in gene and (epi)genome regulation. Because EZH2 deregulation is prevalent in human diseases such as cancer, there is increased dependency on its noncanonical function, which shall have important implications in developing more effective therapeutics.
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Mirzaei S, Gholami MH, Mahabady MK, Nabavi N, Zabolian A, Banihashemi SM, Haddadi A, Entezari M, Hushmandi K, Makvandi P, Samarghandian S, Zarrabi A, Ashrafizadeh M, Khan H. Pre-clinical investigation of STAT3 pathway in bladder cancer: Paving the way for clinical translation. Biomed Pharmacother 2020; 133:111077. [PMID: 33378975 DOI: 10.1016/j.biopha.2020.111077] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
Effective cancer therapy requires identification of signaling networks and investigating their potential role in proliferation and invasion of cancer cells. Among molecular pathways, signal transducer and activator of transcription 3 (STAT3) has been of importance due to its involvement in promoting proliferation, and invasion of cancer cells, and mediating chemoresistance. In the present review, our aim is to reveal role of STAT3 pathway in bladder cancer (BC), as one of the leading causes of death worldwide. In respect to its tumor-promoting role, STAT3 is able to enhance the growth of BC cells via inhibiting apoptosis and cell cycle arrest. STAT3 also contributes to metastasis of BC cells via upregulating of MMP-2 and MMP-9 as well as genes in the EMT pathway. BC cells obtain chemoresistance via STAT3 overexpression and its inhibition paves the way for increasing efficacy of chemotherapy. Different molecular pathways such as KMT1A, EZH2, DAB2IP and non-coding RNAs including microRNAs and long non-coding RNAs can function as upstream mediators of STAT3 that are discussed in this review article.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Noushin Nabavi
- Research Services, University of Victoria, Victoria, BC, V8W 2Y2, Canada
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Amirabbas Haddadi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Pooyan Makvandi
- IstitutoItaliano di Tecnologia, Centre for Micro-BioRobotics, viale Rinaldo Piaggio 34, 56025, Pontedera, Pisa, Italy
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey.
| | - Milad Ashrafizadeh
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey; Faculty of Engineering and Natural Sciences, Sabanci University, OrtaMahalle, ÜniversiteCaddesi No. 27, Orhanlı, Tuzla, 34956, Istanbul, Turkey.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan.
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Yang WS, Kim JH, Jeong D, Hong YH, Park SH, Yang Y, Jang YJ, Kim JH, Cho JY. 3-Deazaadenosine, an S-adenosylhomocysteine hydrolase inhibitor, attenuates lipopolysaccharide-induced inflammatory responses via inhibition of AP-1 and NF-κB signaling. Biochem Pharmacol 2020; 182:114264. [PMID: 33035507 DOI: 10.1016/j.bcp.2020.114264] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/01/2020] [Indexed: 02/08/2023]
Abstract
3-Deazadenosine (3-DA) is a general methylation inhibitor that depletes S-adenosylmethionine, a methyl donor, by blocking S-adenosylhomocysteine hydrolase (SAHH). In this study, we investigated the inhibitory activity and molecular mechanisms of 3-DA in inflammatory responses. 3-DA suppressed the secretion of inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide-treated RAW264.7 cells and phorbol 12-myristate 13-acetate (PMA)-differentiated U937 cells. It also reduced mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β (IL-1 β), and IL-6, indicating that 3-DA has anti-inflammatory properties in murine and human macrophages. Moreover, 3-DA strongly blocked AP-1 and NF-κB luciferase activity under PMA-, MyD88-, and TRIF-stimulated conditions and decreased the translocation of c-Jun, c-Fos, p65, and p50 into the nucleus. In addition, the p-ERK level in AP-1 signaling and the p-IκBα level in NF-kB signaling were diminished by 3-DA treatment. Interestingly, 3-DA did not alter the phosphorylation of MEK1/2, an ERK modulator, or IKKα/β, an IκBα regulator. Instead, 3-DA prevented MEK1/2 and IKKα/β from combining with ERK and IκBα, respectively, and directly suppressed MEK1/2 and IKKα/β kinase activity. These results indicate that MEK1/2 and IKKα/β are direct targets of 3-DA. In addition, suppression of SAHH by siRNA or treatment with adenosine dialdehyde, another SAHH inhibitor, showed inhibitory patterns against p-ERK and IκBα similar to those of 3-DA. Taken together, this study demonstrates that 3-DA inhibits AP-1 and NF-κB signaling by directly blocking MEK1/2 and IKKα/β or indirectly mediating SAHH, resulting in anti-inflammatory activity.
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Affiliation(s)
- Woo Seok Yang
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Ji Hye Kim
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Deok Jeong
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Yo Han Hong
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Sang Hee Park
- Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Yoonyong Yang
- Biological and Genetic Resources Assessment Division, National Institute of Biological Resources, Incheon 22689, Republic of Korea
| | - Young-Jin Jang
- College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Jong-Hoon Kim
- College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea.
| | - Jae Youl Cho
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea; Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Republic of Korea.
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Butturini E, Carcereri de Prati A, Mariotto S. Redox Regulation of STAT1 and STAT3 Signaling. Int J Mol Sci 2020; 21:ijms21197034. [PMID: 32987855 PMCID: PMC7582491 DOI: 10.3390/ijms21197034] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 01/07/2023] Open
Abstract
STAT1 and STAT3 are nuclear transcription factors that regulate genes involved in cell cycle, cell survival and immune response. The cross-talk between these signaling pathways determines how cells integrate the environmental signals received ultimately translating them in transcriptional regulation of specific sets of genes. Despite being activated downstream of common cytokine and growth factors, STAT1 and STAT3 play essentially antagonistic roles and the disruption of their balance directs cells from survival to apoptotic cell death or from inflammatory to anti-inflammatory responses. Different mechanisms are proposed to explain this yin-yang relationship. Considering the redox aspect of STATs proteins, this review attempts to summarize the current knowledge of redox regulation of STAT1 and STAT3 signaling focusing the attention on the post-translational modifications that affect their activity.
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Hou Z, Sun L, Xu F, Hu F, Lan J, Song D, Feng Y, Wang J, Luo X, Hu J, Wang G. Blocking histone methyltransferase SETDB1 inhibits tumorigenesis and enhances cetuximab sensitivity in colorectal cancer. Cancer Lett 2020; 487:63-73. [PMID: 32473242 DOI: 10.1016/j.canlet.2020.05.029] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/12/2020] [Accepted: 05/20/2020] [Indexed: 12/18/2022]
Abstract
The histone methyltransferase SETDB1 catalyzes the addition of methyl groups to histone H3 at lysine 9, and upregulation of SETDB1 is associated with poor prognosis in cancer patients. Here, we describe how overexpression of SETDB1 contributes to colorectal cancer (CRC) tumorigenesis and drug resistance. We show that SETDB1 is upregulated in CRC, and its level correlates with poor clinical outcome. SETDB1 attenuation inhibits CRC cell proliferation Mechanistically, SETDB1 promotes cell proliferation by upregulating Akt activation. Further, SETDB1 is essential for the tumorigenic activity of Akt. Functional characterization revealed that inhibition of SETDB1 reduces cell growth in CRC resistant to targeted treatments in vitro and in vivo, KRAS-mutated CRC included. Taken together, our results indicate that SETDB1 is a major driver of CRC and may serve as a potential target for the treatment of KRAS-mutated CRC.
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Affiliation(s)
- Zhenlin Hou
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China; Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Li Sun
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Feng Xu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fuqing Hu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jingqin Lan
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Da Song
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yongdong Feng
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jing Wang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xuelai Luo
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Junbo Hu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Guihua Wang
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Bharadwaj U, Kasembeli MM, Robinson P, Tweardy DJ. Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution. Pharmacol Rev 2020; 72:486-526. [PMID: 32198236 PMCID: PMC7300325 DOI: 10.1124/pr.119.018440] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Before it was molecularly cloned in 1994, acute-phase response factor or signal transducer and activator of transcription (STAT)3 was the focus of intense research into understanding the mammalian response to injury, particularly the acute-phase response. Although known to be essential for liver production of acute-phase reactant proteins, many of which augment innate immune responses, molecular cloning of acute-phase response factor or STAT3 and the research this enabled helped establish the central function of Janus kinase (JAK) family members in cytokine signaling and identified a multitude of cytokines and peptide hormones, beyond interleukin-6 and its family members, that activate JAKs and STAT3, as well as numerous new programs that their activation drives. Many, like the acute-phase response, are adaptive, whereas several are maladaptive and lead to chronic inflammation and adverse consequences, such as cachexia, fibrosis, organ dysfunction, and cancer. Molecular cloning of STAT3 also enabled the identification of other noncanonical roles for STAT3 in normal physiology, including its contribution to the function of the electron transport chain and oxidative phosphorylation, its basal and stress-related adaptive functions in mitochondria, its function as a scaffold in inflammation-enhanced platelet activation, and its contributions to endothelial permeability and calcium efflux from endoplasmic reticulum. In this review, we will summarize the molecular and cellular biology of JAK/STAT3 signaling and its functions under basal and stress conditions, which are adaptive, and then review maladaptive JAK/STAT3 signaling in animals and humans that lead to disease, as well as recent attempts to modulate them to treat these diseases. In addition, we will discuss how consideration of the noncanonical and stress-related functions of STAT3 cannot be ignored in efforts to target the canonical functions of STAT3, if the goal is to develop drugs that are not only effective but safe. SIGNIFICANCE STATEMENT: Key biological functions of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling can be delineated into two broad categories: those essential for normal cell and organ development and those activated in response to stress that are adaptive. Persistent or dysregulated JAK/STAT3 signaling, however, is maladaptive and contributes to many diseases, including diseases characterized by chronic inflammation and fibrosis, and cancer. A comprehensive understanding of JAK/STAT3 signaling in normal development, and in adaptive and maladaptive responses to stress, is essential for the continued development of safe and effective therapies that target this signaling pathway.
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Affiliation(s)
- Uddalak Bharadwaj
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Moses M Kasembeli
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Prema Robinson
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - David J Tweardy
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
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