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Karmakar A, Augustine ABHR, Thummer RP. Genes as Genome Stabilizers in Pluripotent Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 40095244 DOI: 10.1007/5584_2025_853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Pluripotent stem cells, comprising embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are characterized by their self-renewal capacity and the ability to differentiate into cells of all three germ layers of an adult animal. Out of the two, iPSCs are generated through the reprogramming of somatic cells by inducing a pluripotency-specific transcriptional program. This process requires a resetting of the somatic cell genome to a pluripotent cell-specific genome, resulting in cellular stress at genomic, epigenetic, and transcriptional levels. Notably, in contrast to the predominant compact and inactive organization of chromatin in somatic cells, the chromatin in ESCs and iPSCs is open. Furthermore, maintaining a pluripotent state needs a plethora of changes in the genetic landscape of the cells. Here, we attempt to elucidate how certain genes safeguard genomic stability in ESCs and iPSCs, aiding in the complex cellular mechanisms that regulate self-renewal, pluripotency, and somatic reprogramming.
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Affiliation(s)
- Asmita Karmakar
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Allan Blessing Harison Raj Augustine
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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2
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Kin K, Bhogale S, Zhu L, Thomas D, Bertol J, Zheng WJ, Sinha S, Fakhouri WD. Sequence-to-expression approach to identify etiological non-coding DNA variations in P53 and cMYC-driven diseases. Hum Mol Genet 2024; 33:1697-1710. [PMID: 39017605 PMCID: PMC11413647 DOI: 10.1093/hmg/ddae109] [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: 03/17/2024] [Revised: 06/08/2024] [Accepted: 07/11/2024] [Indexed: 07/18/2024] Open
Abstract
Disease risk prediction based on genomic sequence and transcriptional profile can improve disease screening and prevention. Despite identifying many disease-associated DNA variants, distinguishing deleterious non-coding DNA variations remains poor for most common diseases. In this study, we designed in vitro experiments to uncover the significance of occupancy and competitive binding between P53 and cMYC on common target genes. Analyzing publicly available ChIP-seq data for P53 and cMYC in embryonic stem cells showed that ~344-366 regions are co-occupied, and on average, two cis-overlapping motifs (CisOMs) per region were identified, suggesting that co-occupancy is evolutionarily conserved. Using U2OS and Raji cells untreated and treated with doxorubicin to increase P53 protein level while potentially reducing cMYC level, ChIP-seq analysis illustrated that around 16 to 922 genomic regions were co-occupied by P53 and cMYC, and substitutions of cMYC signals by P53 were detected post doxorubicin treatment. Around 187 expressed genes near co-occupied regions were altered at mRNA level according to RNA-seq data analysis. We utilized a computational motif-matching approach to illustrate that changes in predicted P53 binding affinity in CisOMs of co-occupied elements significantly correlate with alterations in reporter gene expression. We performed a similar analysis using SNPs mapped in CisOMs for P53 and cMYC from ChIP-seq data, and expression of target genes from GTEx portal. We found significant correlation between change in cMYC-motif binding affinity in CisOMs and altered expression. Our study brings us closer to developing a generally applicable approach to filter etiological non-coding variations associated with common diseases.
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Affiliation(s)
- Katherine Kin
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, 7500 Cambridge St, Houston, TX 77054, United States
| | - Shounak Bhogale
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana–Champaign, 600 S Mathews Ave, Urbana, IL 61801, United States
| | - Lisha Zhu
- School of Biomedical Informatics, University of Texas Health Science Center at Houston, 7000 Fannin St #600, Houston, TX 77030, United States
| | - Derrick Thomas
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, 7500 Cambridge St, Houston, TX 77054, United States
| | - Jessica Bertol
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, 7500 Cambridge St, Houston, TX 77054, United States
| | - W Jim Zheng
- School of Biomedical Informatics, University of Texas Health Science Center at Houston, 7000 Fannin St #600, Houston, TX 77030, United States
| | - Saurabh Sinha
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana–Champaign, 600 S Mathews Ave, Urbana, IL 61801, United States
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, North Avenue Atlanta, GA 30332, United States
| | - Walid D Fakhouri
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, 7500 Cambridge St, Houston, TX 77054, United States
- Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX 77030, United States
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Oke A, Manohar SM. Dynamic Roles of Signaling Pathways in Maintaining Pluripotency of Mouse and Human Embryonic Stem Cells. Cell Reprogram 2024; 26:46-56. [PMID: 38635924 DOI: 10.1089/cell.2024.0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024] Open
Abstract
Culturing of mouse and human embryonic stem cells (ESCs) in vitro was a major breakthrough in the field of stem cell biology. These models gained popularity very soon mainly due to their pluripotency. Evidently, the ESCs of mouse and human origin share typical phenotypic responses due to their pluripotent nature, such as self-renewal capacity and potency. The conserved network of core transcription factors regulates these responses. However, significantly different signaling pathways and upstream transcriptional networks regulate expression and activity of these core pluripotency factors in ESCs of both the species. In fact, ample evidence shows that a pathway, which maintains pluripotency in mouse ESCs, promotes differentiation in human ESCs. In this review, we discuss the role of canonical signaling pathways implicated in regulation of pluripotency and differentiation particularly in mouse and human ESCs. We believe that understanding these distinct and at times-opposite mechanisms-is critical for the progress in the field of stem cell biology and regenerative medicine.
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Affiliation(s)
- Anagha Oke
- Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS (Deemed-to-Be) University, Mumbai, Maharashtra, India
| | - Sonal M Manohar
- Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS (Deemed-to-Be) University, Mumbai, Maharashtra, India
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Kin K, Bhogale S, Zhu L, Thomas D, Bertol J, Zheng WJ, Sinha S, Fakhouri WD. Sequence-to-expression approach to identify etiological non-coding DNA variations in P53 and cMYC-driven diseases. RESEARCH SQUARE 2023:rs.3.rs-3037310. [PMID: 37503250 PMCID: PMC10371153 DOI: 10.21203/rs.3.rs-3037310/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Background and methods Disease risk prediction based on DNA sequence and transcriptional profile can improve disease screening, prevention, and potential therapeutic approaches by revealing contributing genetic factors and altered regulatory networks. Despite identifying many disease-associated DNA variants through genome-wide association studies, distinguishing deleterious non-coding DNA variations remains poor for most common diseases. We previously reported that non-coding variations disrupting cis-overlapping motifs (CisOMs) of opposing transcription factors significantly affect enhancer activity. We designed in vitro experiments to uncover the significance of the co-occupancy and competitive binding and inhibition between P53 and cMYC on common target gene expression. Results Analyzing publicly available ChIP-seq data for P53 and cMYC in human embryonic stem cells and mouse embryonic cells showed that ~ 344-366 genomic regions are co-occupied by P53 and cMYC. We identified, on average, two CisOMs per region, suggesting that co-occupancy is evolutionarily conserved in vertebrates. Our data showed that treating U2OS cells with doxorubicin increased P53 protein level while reducing cMYC level. In contrast, no change in protein levels was observed in Raji cells. ChIP-seq analysis illustrated that 16-922 genomic regions were co-occupied by P53 and cMYC before and after treatment, and substitutions of cMYC signals by P53 were detected after doxorubicin treatment in U2OS. Around 187 expressed genes near co-occupied regions were altered at mRNA level according to RNA-seq data. We utilized a computational motif-matching approach to determine that changes in predicted P53 binding affinity by DNA variations in CisOMs of co-occupied elements significantly correlate with alterations in reporter gene expression. We performed a similar analysis using SNPs mapped in CisOMs for P53 and cMYC from ChIP-seq data in U2OS and Raji, and expression of target genes from the GTEx portal. Conclusions We found a significant correlation between change in motif-predicted cMYC binding affinity by SNPs in CisOMs and altered gene expression. Our study brings us closer to developing a generally applicable approach to filter etiological non-coding variations associated with P53 and cMYC-dependent diseases.
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Affiliation(s)
- Katherine Kin
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston
| | | | - Lisha Zhu
- School of Biomedical Informatics, University of Texas Health Science Center at Houston
| | - Derrick Thomas
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston
| | - Jessica Bertol
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston
| | - W Jim Zheng
- School of Biomedical Informatics, University of Texas Health Science Center at Houston
| | - Saurabh Sinha
- The Wallace H. Coulter Department of Biomedical Engineering
| | - Walid D Fakhouri
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston
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Tsujino T, Takai T, Hinohara K, Gui F, Tsutsumi T, Bai X, Miao C, Feng C, Gui B, Sztupinszki Z, Simoneau A, Xie N, Fazli L, Dong X, Azuma H, Choudhury AD, Mouw KW, Szallasi Z, Zou L, Kibel AS, Jia L. CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer. Nat Commun 2023; 14:252. [PMID: 36650183 PMCID: PMC9845315 DOI: 10.1038/s41467-023-35880-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 01/05/2023] [Indexed: 01/18/2023] Open
Abstract
Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.
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Affiliation(s)
- Takuya Tsujino
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Tomoaki Takai
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kunihiko Hinohara
- Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, USA
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fu Gui
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Takeshi Tsutsumi
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Xiao Bai
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Chenkui Miao
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Chao Feng
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Bin Gui
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Zsofia Sztupinszki
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Antoine Simoneau
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Ning Xie
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Ladan Fazli
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Xuesen Dong
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Haruhito Azuma
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Atish D Choudhury
- Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, USA
| | - Kent W Mouw
- Department of Radiation Oncology, Dana-Farber Cancer Institute & Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Zoltan Szallasi
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Lee Zou
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Adam S Kibel
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Li Jia
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
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Gromowski T, Lukacs-Kornek V, Cisowski J. Current view of liver cancer cell-of-origin and proposed mechanisms precluding its proper determination. Cancer Cell Int 2023; 23:3. [PMID: 36609378 PMCID: PMC9824961 DOI: 10.1186/s12935-022-02843-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/30/2022] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.
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Affiliation(s)
- Tomasz Gromowski
- grid.5522.00000 0001 2162 9631Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Veronika Lukacs-Kornek
- grid.10388.320000 0001 2240 3300Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Jaroslaw Cisowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy. SCIENCE CHINA. LIFE SCIENCES 2023; 66:81-93. [PMID: 35881220 DOI: 10.1007/s11427-021-2123-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 04/30/2022] [Indexed: 02/04/2023]
Abstract
The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms, including the hijacking of the tumor suppressors p53 and PP2A. Targeting aberrant SET represents a promising strategy for cancer intervention. However, the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown. Here, we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells. In addition, p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET, whereby SET-mediated inhibition of PP2A was alleviated. Moreover, targeting the interaction between SET and PP2A catalytic subunit (PP2Ac) with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55 (Thr55). Therefore, our findings uncovered a previously unknown p53-SET-PP2A regulatory feedback loop. To functionally potentiate this feedback loop, we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression. Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop.
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Grow EJ, Weaver BD, Smith CM, Guo J, Stein P, Shadle SC, Hendrickson PG, Johnson NE, Butterfield RJ, Menafra R, Kloet SL, van der Maarel SM, Williams CJ, Cairns BR. p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models. Nat Genet 2021; 53:1207-1220. [PMID: 34267371 PMCID: PMC8513633 DOI: 10.1038/s41588-021-00893-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/01/2021] [Indexed: 12/21/2022]
Abstract
In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing and assembly of the mouse Dux locus reveals its complex chromatin regulation including putative positive and negative feedback loops. We show that the p53-DUX/DUX4 regulatory axis is conserved in humans. Furthermore, we demonstrate that cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) activate human DUX4 during p53 signaling via a p53-binding site in a primate-specific subtelomeric long terminal repeat (LTR)10C element. In summary, our work shows that p53 activation convergently evolved to couple p53 to Dux/DUX4 activation in embryonic stem cells, embryos and cells from patients with FSHD, potentially uniting the developmental and disease regulation of DUX-family factors and identifying evidence-based therapeutic opportunities for FSHD.
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Affiliation(s)
- Edward J Grow
- Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Bradley D Weaver
- Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Christina M Smith
- Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Jingtao Guo
- Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
- Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Paula Stein
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - Sean C Shadle
- Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Peter G Hendrickson
- Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Nicholas E Johnson
- Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Russell J Butterfield
- Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Roberta Menafra
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Susan L Kloet
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Carmen J Williams
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - Bradley R Cairns
- Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
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Liu Y, Zhang P, Huang W, Liu F, Long D, Peng W, Dang X, Zeng X, Zhou R. p53 Promotes Differentiation of Cardiomyocytes from hiPSC through Wnt Signaling-Mediated Mesendodermal Differentiation. Int J Stem Cells 2021; 14:410-422. [PMID: 34158418 PMCID: PMC8611312 DOI: 10.15283/ijsc21051] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/11/2021] [Accepted: 05/17/2021] [Indexed: 11/17/2022] Open
Abstract
Background and Objectives Manipulating different signaling pathways via small molecules could efficiently induce cardiomyocytes from human induced pluripotent stem cells (hiPSC). However, the effect of transcription factors on the hiPSC-directed cardiomyocytes differentiation remains unclear. Transcription factor, p53 has been demonstrated indispensable for the early embryonic development and mesendodermal differentiation of embryonic stem cells (ESC). We tested the hypothesis that p53 promotes cardiomyocytes differentiation from human hiPSC. Methods and Results Using the well-characterized GiWi protocol that cardiomyocytes are generated from hiPSC via temporal modulation of Wnt signaling pathway by small molecules, we demonstrated that forced expression of p53 in hiPSC remarkably improved the differentiation efficiency of cardiomyocytes from hiPSC, whereas knockdown endogenous p53 decreased the yield of cardiomyocytes. This p53-mediated increased cardiomyocyte differentiation was mediated through WNT3, as evidenced by that overexpression of p53 upregulated the expression of WNT3, and knockdown of p53 decreased the WNT3 expression. Mechanistic analysis showed that the increased cardiomyocyte differentiation partially depended on the amplified mesendodermal specification resulted from p53-mediated activation of WNT3-mediated Wnt signaling. Consistently, endogenous WNT3 knockdown significantly ameliorated mesendodermal specification and subsequent cardiomyocyte differentiation. Conclusions These results provide a novel insight into the potential effect of p53 on the development and differentiation of cardiomyocyte during embryogenesis.
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Affiliation(s)
- Yuanshu Liu
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti
| | - Peng Zhang
- Department of Anesthesiology, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Wenjun Huang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti.,Shaanxi Institute for Pediatric Diseases, Xi'an Key Laboratory of Children's Health and Diseases, Department of Cardiology, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong
| | - Feng Liu
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti
| | - Dandan Long
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti
| | - Wanling Peng
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti
| | - Xitong Dang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti
| | - Xiaorong Zeng
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti
| | - Rui Zhou
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Insti.,Shaanxi Institute for Pediatric Diseases, Xi'an Key Laboratory of Children's Health and Diseases, Department of Cardiology, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong
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10
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Ghatak D, Das Ghosh D, Roychoudhury S. Cancer Stemness: p53 at the Wheel. Front Oncol 2021; 10:604124. [PMID: 33505918 PMCID: PMC7830093 DOI: 10.3389/fonc.2020.604124] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022] Open
Abstract
The tumor suppressor p53 maintains an equilibrium between self-renewal and differentiation to sustain a limited repertoire of stem cells for proper development and maintenance of tissue homeostasis. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming. A few reports in recent years have indicated that prevalent TP53 oncogenic gain-of-function (GOF) mutations further boosts the stemness properties of cancer cells. In this review, we discuss the role of wild type p53 in regulating pluripotency of normal stem cells and various mechanisms that control the balance between self-renewal and differentiation in embryonic and adult stem cells. We also highlight how inactivating and GOF mutations in p53 stimulate stemness in cancer cells. Further, we have explored the various mechanisms of mutant p53-driven cancer stemness, particularly emphasizing on the non-coding RNA mediated epigenetic regulation. We have also analyzed the association of cancer stemness with other crucial gain-of-function properties of mutant p53 such as epithelial to mesenchymal transition phenotypes and chemoresistance to understand how activation of one affects the other. Given the critical role of cancer stem-like cells in tumor maintenance, cancer progression, and therapy resistance of mutant p53 tumors, targeting them might improve therapeutic efficacy in human cancers with TP53 mutations.
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Affiliation(s)
- Dishari Ghatak
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Damayanti Das Ghosh
- Division of Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
| | - Susanta Roychoudhury
- Division of Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
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11
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Zhu G, Ying Y, Ji K, Duan X, Mai T, Kim J, Li Q, Yu L, Xu Y. p53 coordinates glucose and choline metabolism during the mesendoderm differentiation of human embryonic stem cells. Stem Cell Res 2020; 49:102067. [PMID: 33160274 DOI: 10.1016/j.scr.2020.102067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/23/2020] [Accepted: 10/20/2020] [Indexed: 01/07/2023] Open
Abstract
Metabolism plays crucial roles in the fate decision of human embryonic stem cells (hESCs). Here, we show that the depletion of p53 in hESCs enhances glycolysis and reduces oxidative phosphorylation, and delays mesendoderm differentiation of hESCs. More intriguingly, the disruption of p53 in hESCs leads to dramatic upregulation of phosphatidylcholine and decrease of total choline in both pluripotent and differentiated state of hESCs, suggesting abnormal choline metabolism in the absence of p53. Collectively, our study reveals the indispensable role of p53 in orchestrating both glucose and lipid metabolism to maintain proper hESC identity.
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Affiliation(s)
- Gaoyang Zhu
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong 528308, China
| | - Yue Ying
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Kaiyuan Ji
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China
| | - Xinyue Duan
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China
| | - Taoyi Mai
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China
| | - Jinchul Kim
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China
| | - Qingjiao Li
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China
| | - Lili Yu
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China.
| | - Yang Xu
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China.
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12
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Haidurov A, Budanov AV. Sestrin family - the stem controlling healthy ageing. Mech Ageing Dev 2020; 192:111379. [PMID: 33022334 DOI: 10.1016/j.mad.2020.111379] [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: 04/06/2020] [Revised: 09/04/2020] [Accepted: 09/29/2020] [Indexed: 01/18/2023]
Abstract
Sestrins are a family of stress-responsive antioxidant proteins responsible for regulation of cell viability and metabolism. The best known Sestrin targets are mTORC1 and mTORC2 kinases that control different cellular processes including growth, viability, autophagy, and mitochondrial metabolism. Inactivation of the single Sestrin gene in invertebrates has an adverse impact on their healthspan and longevity, whereas each of the three Sestrin genes in mammals and other vertebrate organisms has a different impact on maintenance of a particular tissue, affecting its stress tolerance, function and regenerative capability. As a result, Sestrins attenuate ageing and suppress development of many age-related diseases including myocardial infarction, muscle atrophy, diabetes, and immune dysfunction, but exacerbate development of chronic obstructive pulmonary disease. Moreover, Sestrins play opposite roles in carcinogenesis in different tissues. Stem cells support tissue remodelling that influences ageing, and Sestrins might suppress ageing and age-related pathologies through control of stem cell biology. In this review, we will discuss the potential link between Sestrins, stem cells, and ageing.
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Affiliation(s)
- Alexander Haidurov
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Andrei V Budanov
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
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13
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Sammons MA, Nguyen TAT, McDade SS, Fischer M. Tumor suppressor p53: from engaging DNA to target gene regulation. Nucleic Acids Res 2020; 48:8848-8869. [PMID: 32797160 PMCID: PMC7498329 DOI: 10.1093/nar/gkaa666] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 07/24/2020] [Accepted: 07/30/2020] [Indexed: 12/13/2022] Open
Abstract
The p53 transcription factor confers its potent tumor suppressor functions primarily through the regulation of a large network of target genes. The recent explosion of next generation sequencing protocols has enabled the study of the p53 gene regulatory network (GRN) and underlying mechanisms at an unprecedented depth and scale, helping us to understand precisely how p53 controls gene regulation. Here, we discuss our current understanding of where and how p53 binds to DNA and chromatin, its pioneer-like role, and how this affects gene regulation. We provide an overview of the p53 GRN and the direct and indirect mechanisms through which p53 affects gene regulation. In particular, we focus on delineating the ubiquitous and cell type-specific network of regulatory elements that p53 engages; reviewing our understanding of how, where, and when p53 binds to DNA and the mechanisms through which these events regulate transcription. Finally, we discuss the evolution of the p53 GRN and how recent work has revealed remarkable differences between vertebrates, which are of particular importance to cancer researchers using mouse models.
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Affiliation(s)
- Morgan A Sammons
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA
| | - Thuy-Ai T Nguyen
- Genome Integrity & Structural Biology Laboratory and Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA
| | - Simon S McDade
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK
| | - Martin Fischer
- Computational Biology Group, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany
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14
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Cui Y, Cui Z, Xu J, Hao D, Shi J, Wang D, Xiao H, Duan X, Chen R, Li W. NG-Circos: next-generation Circos for data visualization and interpretation. NAR Genom Bioinform 2020; 2:lqaa069. [PMID: 33575618 PMCID: PMC7671351 DOI: 10.1093/nargab/lqaa069] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 08/04/2020] [Accepted: 08/25/2020] [Indexed: 12/23/2022] Open
Abstract
Circos plots are widely used to display multi-dimensional next-generation genomic data, but existing implementations of Circos are not interactive with limited support of data types. Here, we developed next-generation Circos (NG-Circos), a flexible JavaScript-based circular genome visualization tool for designing highly interactive Circos plots using 21 functional modules with various data types. To our knowledge, NG-Circos is the most powerful software to construct interactive Circos plots. By supporting diverse data types in a dynamic browser interface, NG-Circos will accelerate the next-generation data visualization and interpretation, thus promoting the reproducible research in biomedical sciences and beyond. NG-Circos is available at https://wlcb.oit.uci.edu/NG-Circos and https://github.com/YaCui/NG-Circos.
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Affiliation(s)
- Ya Cui
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA
| | - Zhe Cui
- Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jianfeng Xu
- Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Dapeng Hao
- Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jiejun Shi
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA
| | - Dan Wang
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095, USA
| | - Hui Xiao
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA
| | - Xiaohong Duan
- ChosenMed Technology (Beijing) Co. Ltd, Beijing 100176, China
| | - Runsheng Chen
- CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101,China
| | - Wei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA
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15
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Induced pluripotent stem cells of patients with Tetralogy of Fallot reveal transcriptional alterations in cardiomyocyte differentiation. Sci Rep 2020; 10:10921. [PMID: 32616843 PMCID: PMC7331606 DOI: 10.1038/s41598-020-67872-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/16/2020] [Indexed: 12/27/2022] Open
Abstract
Patient-specific induced pluripotent stem cells (ps-iPSCs) and their differentiated cell types are a powerful model system to gain insight into mechanisms driving early developmental and disease-associated regulatory networks. In this study, we use ps-iPSCs to gain insights into Tetralogy of Fallot (TOF), which represents the most common cyanotic heart defect in humans. iPSCs were generated and further differentiated to cardiomyocytes (CMs) using standard methods from two well-characterized TOF patients and their healthy relatives serving as controls. Patient-specific expression patterns and genetic variability were investigated using whole genome and transcriptome sequencing data. We first studied the clonal mutational burden of the derived iPSCs. In two out of three iPSC lines of patient TOF-01, we found a somatic mutation in the DNA-binding domain of tumor suppressor P53, which was not observed in the genomic DNA from blood. Further characterization of this mutation showed its functional impact. For patient TOF-02, potential disease-relevant differential gene expression between and across cardiac differentiation was shown. Here, clear differences at the later stages of differentiation could be observed between CMs of the patient and its controls. Overall, this study provides first insights into the complex molecular mechanisms underlying iPSC-derived cardiomyocyte differentiation and its transcriptional alterations in TOF.
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16
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Perrigue PM, Rakoczy M, Pawlicka KP, Belter A, Giel-Pietraszuk M, Naskręt-Barciszewska M, Barciszewski J, Figlerowicz M. Cancer Stem Cell-Inducing Media Activates Senescence Reprogramming in Fibroblasts. Cancers (Basel) 2020; 12:cancers12071745. [PMID: 32629974 PMCID: PMC7409320 DOI: 10.3390/cancers12071745] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 06/26/2020] [Indexed: 01/05/2023] Open
Abstract
Cellular senescence is a tumor-suppressive mechanism blocking cell proliferation in response to stress. However, recent evidence suggests that senescent tumor cells can re-enter the cell cycle to become cancer stem cells, leading to relapse after cancer chemotherapy treatment. Understanding how the senescence reprogramming process is a precursor to cancer stem cell formation is of great medical importance. To study the interplay between senescence, stemness, and cancer, we applied a stem cell medium (SCM) to human embryonic fibroblasts (MRC5 and WI-38) and cancer cell lines (A549 and 293T). MRC5 and WI-38 cells treated with SCM showed symptoms of oxidative stress and became senescent. Transcriptome analysis over a time course of SCM-induced senescence, revealed a developmental process overlapping with the upregulation of genes for growth arrest and the senescence-associated secretory phenotype (SASP). We demonstrate that histone demethylases jumonji domain-containing protein D3 (Jmjd3) and ubiquitously transcribed tetratricopeptide repeat, X chromosome (Utx), which operate by remodeling chromatin structure, are implicated in the senescence reprogramming process to block stem cell formation in fibroblasts. In contrast, A549 and 293T cells cultured in SCM were converted to cancer stem cells that displayed the phenotype of senescence uncoupled from growth arrest. The direct overexpression of DNA methyltransferases (Dnmt1 and Dnmt3A), ten-eleven translocation methylcytosine dioxygenases (Tet1 and Tet3), Jmjd3, and Utx proteins could activate senescence-associated beta-galactosidase (SA-β-gal) activity in 293T cells, suggesting that epigenetic alteration and chromatin remodeling factors trigger the senescence response. Overall, our study suggests that chromatin machinery controlling senescence reprogramming is significant in cancer stem cell formation.
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Affiliation(s)
- Patrick M. Perrigue
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
- Correspondence: ; Tel.: +48-61-852-85-03
| | - Magdalena Rakoczy
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
| | - Kamila P. Pawlicka
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
| | - Agnieszka Belter
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
| | - Małgorzata Giel-Pietraszuk
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
| | - Mirosława Naskręt-Barciszewska
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
| | - Jan Barciszewski
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
- NanoBioMed Center, Adam Mickiewicz University, Wszechnicy Piastowskiej 3, 61-614 Poznań, Poland
| | - Marek Figlerowicz
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland; (M.R.); (K.P.P.); (A.B.); (M.G.-P.); (M.N.-B.); (J.B.); (M.F.)
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17
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Kafer GR, Cesare AJ. A Survey of Essential Genome Stability Genes Reveals That Replication Stress Mitigation Is Critical for Peri-Implantation Embryogenesis. Front Cell Dev Biol 2020; 8:416. [PMID: 32548123 PMCID: PMC7274024 DOI: 10.3389/fcell.2020.00416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/05/2020] [Indexed: 12/16/2022] Open
Abstract
Murine development demands that pluripotent epiblast stem cells in the peri-implantation embryo increase from approximately 120 to 14,000 cells between embryonic days (E) 4.5 and E7.5. This is possible because epiblast stem cells can complete cell cycles in under 3 h in vivo. To ensure conceptus fitness, epiblast cells must undertake this proliferative feat while maintaining genome integrity. How epiblast cells maintain genome health under such an immense proliferation demand remains unclear. To illuminate the contribution of genome stability pathways to early mammalian development we systematically reviewed knockout mouse data from 347 DDR and repair associated genes. Cumulatively, the data indicate that while many DNA repair functions are dispensable in embryogenesis, genes encoding replication stress response and homology directed repair factors are essential specifically during the peri-implantation stage of early development. We discuss the significance of these findings in the context of the unique proliferative demands placed on pluripotent epiblast stem cells.
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Affiliation(s)
| | - Anthony J. Cesare
- Genome Integrity Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW, Australia
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18
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Hafner A, Kublo L, Tsabar M, Lahav G, Stewart-Ornstein J. Identification of universal and cell-type specific p53 DNA binding. BMC Mol Cell Biol 2020; 21:5. [PMID: 32070277 PMCID: PMC7027055 DOI: 10.1186/s12860-020-00251-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/11/2020] [Indexed: 01/09/2023] Open
Abstract
Background The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell-type specific gene expression programs. However recent studies and meta-analyses of genomic data propose largely uniform, and condition independent p53 binding and thus question the selective and cell-type dependent function of p53. Results To systematically assess the cell-type specificity of p53, we measured its association with DNA in 12 p53 wild-type cancer cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. Conclusions Our study reconciles previous conflicting views in the p53 field, by demonstrating that although the majority of p53 DNA binding is conserved across cell types, there is a small set of cell line specific binding sites that depend on cell state.
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Affiliation(s)
- Antonina Hafner
- Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA. .,Department of Developmental Biology, Stanford University, Stanford, CA, 94305, USA.
| | - Lyubov Kublo
- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Michael Tsabar
- Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Galit Lahav
- Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Jacob Stewart-Ornstein
- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.,Department of Computational and Systems Biology, University of Pittsburgh Medical School, Pittsburgh, PA, 15260, USA
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19
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Ghandhi SA, Smilenov L, Shuryak I, Pujol-Canadell M, Amundson SA. Discordant gene responses to radiation in humans and mice and the role of hematopoietically humanized mice in the search for radiation biomarkers. Sci Rep 2019; 9:19434. [PMID: 31857640 PMCID: PMC6923394 DOI: 10.1038/s41598-019-55982-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 12/05/2019] [Indexed: 12/12/2022] Open
Abstract
The mouse (Mus musculus) is an extensively used model of human disease and responses to stresses such as ionizing radiation. As part of our work developing gene expression biomarkers of radiation exposure, dose, and injury, we have found many genes are either up-regulated (e.g. CDKN1A, MDM2, BBC3, and CCNG1) or down-regulated (e.g. TCF4 and MYC) in both species after irradiation at ~4 and 8 Gy. However, we have also found genes that are consistently up-regulated in humans and down-regulated in mice (e.g. DDB2, PCNA, GADD45A, SESN1, RRM2B, KCNN4, IFI30, and PTPRO). Here we test a hematopoietically humanized mouse as a potential in vivo model for biodosimetry studies, measuring the response of these 14 genes one day after irradiation at 2 and 4 Gy, and comparing it with that of human blood irradiated ex vivo, and blood from whole body irradiated mice. We found that human blood cells in the hematopoietically humanized mouse in vivo environment recapitulated the gene expression pattern expected from human cells, not the pattern seen from in vivo irradiated normal mice. The results of this study support the use of hematopoietically humanized mice as an in vivo model for screening of radiation response genes relevant to humans.
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Affiliation(s)
- Shanaz A Ghandhi
- Columbia University Irving Medical Center, 630 W 168th street, VC11-237, New York, NY, 10032, USA.
| | - Lubomir Smilenov
- Columbia University Irving Medical Center, 630 W 168th street, VC11-237, New York, NY, 10032, USA
| | - Igor Shuryak
- Columbia University Irving Medical Center, 630 W 168th street, VC11-237, New York, NY, 10032, USA
| | - Monica Pujol-Canadell
- Columbia University Irving Medical Center, 630 W 168th street, VC11-237, New York, NY, 10032, USA
| | - Sally A Amundson
- Columbia University Irving Medical Center, 630 W 168th street, VC11-237, New York, NY, 10032, USA
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20
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Gao SW, Liu F. Novel insights into cell cycle regulation of cell fate determination. J Zhejiang Univ Sci B 2019; 20:467-475. [PMID: 31090272 DOI: 10.1631/jzus.b1900197] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The stem/progenitor cell has long been regarded as a central cell type in development, homeostasis, and regeneration, largely owing to its robust self-renewal and multilineage differentiation abilities. The balance between self-renewal and stem/progenitor cell differentiation requires the coordinated regulation of cell cycle progression and cell fate determination. Extensive studies have demonstrated that cell cycle states determine cell fates, because cells in different cell cycle states are characterized by distinct molecular features and functional outputs. Recent advances in high-resolution epigenome profiling, single-cell transcriptomics, and cell cycle reporter systems have provided novel insights into the cell cycle regulation of cell fate determination. Here, we review recent advances in cell cycle-dependent cell fate determination and functional heterogeneity, and the application of cell cycle manipulation for cell fate conversion. These findings will provide insight into our understanding of cell cycle regulation of cell fate determination in this field, and may facilitate its potential application in translational medicine.
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Affiliation(s)
- Su-Wei Gao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Feng Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing 100049, China
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21
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Zhang G, Xu Y, Zou C, Tang Y, Lu J, Gong Z, Ma G, Zhang W, Jiang P. Long noncoding RNA ARHGAP27P1 inhibits gastric cancer cell proliferation and cell cycle progression through epigenetically regulating p15 and p16. Aging (Albany NY) 2019; 11:9090-9110. [PMID: 31665700 PMCID: PMC6834409 DOI: 10.18632/aging.102377] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 10/14/2019] [Indexed: 01/23/2023]
Abstract
Long noncoding RNAs (lncRNAs) have emerged as important regulators in the development and progression of gastric cancer (GC). ARHGAP27P1 is a pseudogene-derived lncRNA, and it has been found to be associated with GC in our preliminary study, but this association has not been studied further. Herein, we confirmed that ARHGAP27P1 was significantly downregulated in GC tissues, plasma and cells. Low expression of ARHGAP27P1 was closely associated with advanced TNM stage, increased invasion depth and lymphatic metastasis. Low ARHGAP27P1 expression also predicted a poor prognosis in GC patients. Functionally, overexpression of ARHGAP27P1 inhibited proliferation, invasion, and migration in GC cells, while silencing of ARHGAP27P1 showed the opposite effects. Mechanistic investigations showed that ARHGAP27P1 had a key role in G0/G1 arrest. We further demonstrated that ARHGAP27P1 was associated with Jumonji-domain containing 3 (JMJD3) and that this association was required for the demethylation of H3K27me3, thereby epigenetically activating expression of p15, p16 and p57. Moreover, knockdown of JMJD3, p15, or p16 consistently reversed the inhibitory effects of ARHGAP27P1 in cell proliferation and cell cycle progression. Taken together, these results suggest that lncRNA ARHGAP27P1, as a novel cell cycle regulator, may serve as a potential target for GC prevention and treatment in human GC.
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Affiliation(s)
- Guohua Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.,Department of General Surgery, Peony People's Hospital, Heze, China
| | - Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Zou
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Yinbing Tang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jiawei Lu
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Zhigang Gong
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Gui Ma
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
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22
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Nguyen TAT, Grimm SA, Bushel PR, Li J, Li Y, Bennett BD, Lavender CA, Ward JM, Fargo DC, Anderson CW, Li L, Resnick MA, Menendez D. Revealing a human p53 universe. Nucleic Acids Res 2019; 46:8153-8167. [PMID: 30107566 PMCID: PMC6144829 DOI: 10.1093/nar/gky720] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 07/27/2018] [Indexed: 12/13/2022] Open
Abstract
p53 transcriptional networks are well-characterized in many organisms. However, a global understanding of requirements for in vivo p53 interactions with DNA and relationships with transcription across human biological systems in response to various p53 activating situations remains limited. Using a common analysis pipeline, we analyzed 41 data sets from genome-wide ChIP-seq studies of which 16 have associated gene expression data, including our recent primary data with normal human lymphocytes. The resulting extensive analysis, accessible at p53 BAER hub via the UCSC browser, provides a robust platform to characterize p53 binding throughout the human genome including direct influence on gene expression and underlying mechanisms. We establish the impact of spacers and mismatches from consensus on p53 binding in vivo and propose that once bound, neither significantly influences the likelihood of expression. Our rigorous approach revealed a large p53 genome-wide cistrome composed of >900 genes directly targeted by p53. Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment- or cell-specific, demonstrating new functions for p53 in cell biology. Our analysis reveals a broad homeostatic role for human p53 that is relevant to both basic and translational studies.
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Affiliation(s)
- Thuy-Ai T Nguyen
- Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Sara A Grimm
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Pierre R Bushel
- Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Jianying Li
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Yuanyuan Li
- Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Brian D Bennett
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Christopher A Lavender
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - James M Ward
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - David C Fargo
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA.,Office of Scientific Computing, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Carl W Anderson
- Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Leping Li
- Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Michael A Resnick
- Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Daniel Menendez
- Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA
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23
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The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Exp Mol Med 2019; 51:1-17. [PMID: 31221981 PMCID: PMC6586683 DOI: 10.1038/s12276-019-0230-6] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 12/12/2018] [Indexed: 12/16/2022] Open
Abstract
Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development. The cancer genome atlas (TCGA) project identified 299 genes and 24 pathways/biological processes that drive tumor progression (Cell 173: 371-385 e318, 2018). Of the 299 driver genes, 12 genes are involved in histones, histone methylation, and demethylation. Among these 12 genes, those encoding the histone demethylases JARID1C/KDM5C and UTX/KDM6A were identified as cancer driver genes. Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of α-ketoglutarate, O2-dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases. Studies on oncometabolites suggest that histone demethylases mediate metabolic changes in chromatin structure. We have reviewed the most recent findings regarding cancer-specific metabolic reprogramming and the tumor-suppressive roles of JARID1C/KDM5C and UTX/KDM6A. We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type. Genes involved in the removal of methyl groups from histones associated with DNA can promote or suppress tumor growth depending on the metabolic status of the cancer cell. Hyunsung Park and colleagues at the University of Seoul, South Korea, review current knowledge of two genes encoding histone demethylases which have been identified by The Cancer Genome Atlas (TCGA) project as cancer driver genes. Because these demethylase enzymes rely on cellular metabolites to function, their effect is influenced by metabolic conditions in the tumor microenvironment such as low oxygen. The mechanisms through which changes in histone methylation affect the expression of genes involved in tumor progression remain unknown. Further understanding of how cancer metabolism affects the modification of histones will help guide the development of more effective cancer treatments.
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24
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Rastogi A, Joshi P, Contreras E, Gama V. Remodeling of mitochondrial morphology and function: an emerging hallmark of cellular reprogramming. Cell Stress 2019; 3:181-194. [PMID: 31225513 PMCID: PMC6558935 DOI: 10.15698/cst2019.06.189] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Research in the stem cell field has traditionally focused on understanding key transcriptional factors that provide pluripotent cell identity. However, much less is known about other critical non-transcriptional signaling networks that govern stem cell identity. Although we continue to gain critical insights into the mechanisms underlying mitochondrial morphology and function during cellular reprogramming – the process of reverting the fate of a differentiated cell into a stem cell, many uncertainties remain. Recent studies suggest an emerging landscape in which mitochondrial morphology and function have an active role in maintaining and regulating changes in cell identity. In this review, we will focus on these emerging concepts as crucial modulators of cellular reprogramming. Recognition of the widespread applicability of these concepts will increase our understanding of the mitochondrial mechanisms involved in cell identity, cell fate and disease.
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Affiliation(s)
- Anuj Rastogi
- Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37240
| | - Piyush Joshi
- Neuroscience Program, Vanderbilt University Medical Center, Nashville, TN 37240.,Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37240
| | - Ela Contreras
- Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37240
| | - Vivian Gama
- Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37240.,Neuroscience Program, Vanderbilt University Medical Center, Nashville, TN 37240.,Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37240.,Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37240
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25
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Kurtz P, Jones AE, Tiwari B, Link N, Wylie A, Tracy C, Krämer H, Abrams JM. Drosophila p53 directs nonapoptotic programs in postmitotic tissue. Mol Biol Cell 2019; 30:1339-1351. [PMID: 30892991 PMCID: PMC6724604 DOI: 10.1091/mbc.e18-12-0791] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/06/2019] [Accepted: 03/13/2019] [Indexed: 12/26/2022] Open
Abstract
TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We recently showed that a p53 enhancer (p53RErpr) near the cell death gene reaper forms chromatin contacts and enables p53 target activation across long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in adult heads. Moreover, this failure to exhibit apoptotic responses was not associated with altered chromatin contacts. Instead, we determined that p53 does not occupy the p53RErpr enhancer in this postmitotic tissue as it does in embryos. Through comparative RNA-seq and chromatin immunoprecipitation-seq studies of developing and postmitotic tissues, we further determined that p53 regulates distinct transcriptional programs in adult heads, including DNA repair, metabolism, and proteolysis genes. Strikingly, in the postmitotic context, p53-binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.
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Affiliation(s)
- Paula Kurtz
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Amanda E. Jones
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Bhavana Tiwari
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Nichole Link
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030
- Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030
| | - Annika Wylie
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Charles Tracy
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Helmut Krämer
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - John M. Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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26
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Lin T, Hou PF, Meng S, Chen F, Jiang T, Li ML, Shi ML, Liu JJ, Zheng JN, Bai J. Emerging Roles of p53 Related lncRNAs in Cancer Progression: A Systematic Review. Int J Biol Sci 2019; 15:1287-1298. [PMID: 31223287 PMCID: PMC6567798 DOI: 10.7150/ijbs.33218] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022] Open
Abstract
p53 is the major mediator of the tumor suppressor response. It participates in apoptosis and senescence and can respond to DNA damage. As a crucial sequence-specific transcription factor, p53 regulates the expression of many genes, such as small noncoding RNAs (ncRNAs), microRNAs, and long ncRNAs (lncRNAs). Given the emergence of novel and high-throughput sequencing technologies, many lncRNAs have been discovered. LncRNAs may function as vital gene regulators in a variety of biological processes through extensive mechanisms. Recently, lncRNAs have been demonstrated to be associated with the p53 regulatory pathway. In this review, we discuss the current and fast growing knowledge about the influence of lncRNAs to the p53 signaling pathway, the different mechanisms by which they affect gene expression in cancer. Our findings show that p53-associated lncRNAs may be used as biomarkers for cancer diagnosis or targets for disease therapy.
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Affiliation(s)
- Tian Lin
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Ping-Fu Hou
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Sen Meng
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Fang Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Tao Jiang
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Min-Le Li
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Mei-Lin Shi
- School of Medical Imaging, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jin-Jin Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Jun-Nian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
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Gasiūnienė M, Zubova A, Utkus A, Navakauskienė R. Epigenetic and metabolic alterations in human amniotic fluid stem cells induced to cardiomyogenic differentiation by DNA methyltransferases and p53 inhibitors. J Cell Biochem 2019; 120:8129-8143. [PMID: 30485506 DOI: 10.1002/jcb.28092] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 10/29/2018] [Indexed: 01/24/2023]
Abstract
Human amniotic fluid-derived mesenchymal stem cells (AF-MSCs) may be a valuable source for cell therapy and regenerative medicine. In this study, the potential of DNA methyltransferases (DNMT) inhibitors Decitabine, Zebularine, RG108 alone or combined with Zebularine and p53 inhibitor Pifithrin-α to induce cardiomyogenic differentiation of AF-MSCs was investigated. Differentiation into cardiomyocyte-like cells initiation was indicated with all agents by changes in the cell phenotype, upregulation of the relative expression of the main cardiac genes (NKX2-5, TNNT2, MYH6, and DES) as well as of cardiac ion channels genes (sodium, calcium, and potassium) as determined by reverse-transcription quantitative polymerase chain reaction and the increase in Connexin43 levels as detected from Western blot and immunofluorescence data. Cellular energetics and mitochondrial function in induced cells were assessed using Seahorse analyzer and revealed the initiation of AF-MSCs metabolic transformation into cardiomyocyte-like cells. All used inducers were nontoxic to AF-MSCs, arrested cell cycle at the G0/G1 phase, and upregulated p53 and p21 expression. The relative expression of miR-34a and miR-145 that are related to cell cycle regulation was also observed. Furthermore, the evaluated levels of chromatin remodeling proteins enhancer of zeste homolog 2, suppressor of zeste 12 protein homolog, DNMT1, histone deacetylase 1 (HDAC1), HDAC2, and heterochromatin protein 1α, as well as the rate of activating histone modifications, exhibited rearrangements of chromatin after the induction of cardiomyogenic differentiation. In conclusion, we demonstrated that all explored DNMT and p53 inhibitors initiated cardiomyogenesis-related alterations in AF-MSCs through rather similar mechanisms but to a different extent providing useful insights for the future research and potential applications of AF-MSCs.
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Affiliation(s)
- Monika Gasiūnienė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Anastasija Zubova
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Algirdas Utkus
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Rūta Navakauskienė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
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28
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Wang H, Zhao S, Barton M, Rosengart T, Cooney AJ. Reciprocity of Action of Increasing Oct4 and Repressing p53 in Transdifferentiation of Mouse Embryonic Fibroblasts into Cardiac Myocytes. Cell Reprogram 2019; 20:27-37. [PMID: 29412738 DOI: 10.1089/cell.2017.0031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
p53 is a barrier to somatic cell reprogramming. Deletion or transient suppression of p53 increases the efficiency of reprogramming of somatic cells into induced pluripotent stem cells. Whether p53 represents an obstacle to a similar process transdifferentiation of somatic cells is unknown. However, it is predicted that inhibition of p53 would promote transdifferentiation of fibroblasts into cardiomyocytes. In this study, the effect of p53 on the capacity of cardiogenic transdifferentiation is evaluated using p53 wild-type (p53+/+), p53 heterozygous mutant (p53+/-), and p53 homozygous mutant (p53-/-) mouse embryonic fibroblasts (MEFs). Repression of p53 in MEFs increases the expression level of mesoderm transcription factors Brachyury (T) and MESP1. The cardiac-specific markers, Myh6 (Myosin, Heavy Chain 6), Myh7 (Myosin, Heavy Chain 7), and cTnI (cardiac muscle troponin I), show elevated expression in p53+/- and p53-/- MEFs compared with wild-type MEFs, but cardiac muscle troponin T (cTnT) showed a lower expression level when p53 was inhibited. After induction to cardiac differentiation, cTnT expression increased and markers of endoderm and ectoderm decreased in p53+/- and p53-/- MEFs. The effect of an important reprogramming factor Oct4 on cardiac transdifferentiation was also evaluated in the allelic series of p53 MEFs. We found that overexpression of Oct4 significantly enhanced Mesp1, Tbx5, and Isl1 expression in p53+/+ and p53+/- MEFs. Oct4 also enhanced cTnT expression in all three cell lines, especially in p53+/- MEFs. Thus, inhibition of p53 expression and viral expression of Oct4 both promote transdifferentiation of MEFs into cardiomyocytes, establishing reciprocity of action in the process.
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Affiliation(s)
- Hongran Wang
- 1 Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School , Austin, Texas
| | - Shuying Zhao
- 1 Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School , Austin, Texas
| | - Michelle Barton
- 2 Department of Epigenetics and Molecular Carcinogenesis, Center for Stem Cell and Developmental Biology, UT MD Anderson Cancer Center , Houston, Texas
| | - Todd Rosengart
- 3 Department of Surgery, Baylor College of Medicine , Houston, Texas
| | - Austin J Cooney
- 1 Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School , Austin, Texas
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29
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Chen H, Huang Y, Zhu X, Liu C, Yuan Y, Su H, Zhang C, Liu C, Xiong M, Qu Y, Yun P, Zheng L, Huang K. Histone demethylase UTX is a therapeutic target for diabetic kidney disease. J Physiol 2019; 597:1643-1660. [PMID: 30516825 PMCID: PMC6418754 DOI: 10.1113/jp277367] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 11/26/2018] [Indexed: 12/23/2022] Open
Abstract
KEY POINTS Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid-induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK-J4 treatment showed the opposite effects. We found that UTX demethylase activity-dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. ABSTRACT Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end-stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di- and tri-methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK-J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity-dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.
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Affiliation(s)
- Hong Chen
- Tongji School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yixue Huang
- Tongji School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiuqin Zhu
- Hubei Key Laboratory of Cell HomeostasisCollege of Life SciencesWuhan UniversityWuhanChina
| | - Chong Liu
- Hubei Key Laboratory of Cell HomeostasisCollege of Life SciencesWuhan UniversityWuhanChina
| | - Yangmian Yuan
- Hubei Key Laboratory of Cell HomeostasisCollege of Life SciencesWuhan UniversityWuhanChina
| | - Hua Su
- Department of NephrologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chun Zhang
- Department of NephrologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chengyu Liu
- Tongji School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Mingrui Xiong
- Tongji School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yannan Qu
- Hubei Key Laboratory of Cell HomeostasisCollege of Life SciencesWuhan UniversityWuhanChina
| | - Peng Yun
- The First People's Hospital of JingzhouJingzhouChina
| | - Ling Zheng
- Hubei Key Laboratory of Cell HomeostasisCollege of Life SciencesWuhan UniversityWuhanChina
| | - Kun Huang
- Tongji School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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30
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Hafner A, Bulyk ML, Jambhekar A, Lahav G. The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol 2019; 20:199-210. [DOI: 10.1038/s41580-019-0110-x] [Citation(s) in RCA: 452] [Impact Index Per Article: 75.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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31
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Abstract
Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine 27 (H3K27). UTX function has been linked to homeotic gene expression, embryonic development, and cellular reprogramming. UTX and its protein interactors within the COMPASS family, including the MLL3 and MLL4 lysine methyltransferases, are frequently mutated in multiple human cancers; however, the molecular basis of how these mutations contribute to oncogenesis remains unclear. Here, we discuss catalytic-dependent and -independent functions of UTX and its partners MLL3 and MLL4 as part of the COMPASS family during development and in oncogenesis.
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Affiliation(s)
- Lu Wang
- Simpson Querrey Center for Epigenetics, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Searle 6-512, 320 E. Superior St., Chicago, IL 60611, USA
| | - Ali Shilatifard
- Simpson Querrey Center for Epigenetics, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Searle 6-512, 320 E. Superior St., Chicago, IL 60611, USA.
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32
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Schulz WA, Lang A, Koch J, Greife A. The histone demethylase UTX/KDM6A in cancer: Progress and puzzles. Int J Cancer 2019; 145:614-620. [PMID: 30628063 DOI: 10.1002/ijc.32116] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/11/2018] [Accepted: 01/07/2019] [Indexed: 01/01/2023]
Abstract
The lysine-specific demethylase 6A/UTX (gene name KDM6A) acts as a component of the COMPASS complex to control gene activation. UTX demethylates H3K27me2/3 at genes and enhancers. Deleterious mutations in KDM6A are found in many cancer types, prominently urothelial carcinoma and certain T-cell leukemias. In certain cancers, however, UTX supports oncogenic transcription factors, e.g. steroid hormone receptors in breast and prostate cancer. In fetal development, UTX regulates lineage choice and cell differentiation. Analogously, loss of UTX function in cancer may lead to metaplasia or impede differentiation. Likely because its function is contingent on its interacting transcription factors, the effects of UTX inactivation are not uniform and require detailed investigation in each cancer type. In urothelial carcinoma, in particular, the functional consequences of the frequent mutations in KDM6A and other COMPASS component genes are poorly understood. Nevertheless, UTX inactivation appears to sensitize many cancers to inhibitors of the H3K27 methyltransferase EZH2. Conversely, inhibitors of UTX enzymatic activity may be applicable in cancers with an oncogenic UTX function. Intriguingly, the fact that KDM6A is localized on the X-chromosome, but both copies are expressed, may account for gender-specific differences in cancer susceptibility. In conclusion, despite recent progress, many open questions need to be addressed, most importantly, the detailed mechanisms by which KDM6A inactivation promotes various cancers, but also with which proteins UTX interacts in and apart from the COMPASS complex, and to which extent its catalytic function is required for its tumor-suppressive function.
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Affiliation(s)
- Wolfgang A Schulz
- Department of Urology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Alexander Lang
- Department of Urology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Julian Koch
- Department of Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Annemarie Greife
- Department of Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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33
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JMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML. Nat Commun 2018; 9:3369. [PMID: 30135572 PMCID: PMC6105679 DOI: 10.1038/s41467-018-05548-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 06/29/2018] [Indexed: 12/21/2022] Open
Abstract
JMJD3, a stress-inducible H3K27 demethylase, plays a critical regulatory role in the initiation and progression of malignant hematopoiesis. However, how this histone modifier affects in a cell type-dependent manner remains unclear. Here, we show that in contrast to its oncogenic effect in preleukemia state and lymphoid malignancies, JMJD3 relieves the differentiation-arrest of certain subtypes (such as M2 and M3) of acute myeloid leukemia (AML) cells. RNA sequencing and ChIP−PCR analyses revealed that JMJD3 exerts anti-AML effect by directly modulating H3K4 and H3K27 methylation levels to activate the expression of a number of key myelopoietic regulatory genes. Mechanistic exploration identified a physical and functional association of JMJD3 with C/EBPβ that presides the regulatory network of JMJD3. Thus, the leukemia regulatory role of JMJD3 varies in a disease phase- and lineage-dependent manner, and acts as a potential oncorepressor in certain subsets of AML largely by coupling to C/EBPβ-centered myelopoietic program. Histone demethylase JMJD3 is known to be oncogenic in preleukemic states and T-cell acute lymphocytic leukemia. Here, the authors show that in some acute myeloid leukemia subsets, JMJD3 can actually act as a potential oncorepressor via mediation of C/EBPβ-centered transcriptional programming.
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34
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Zhu H, Wang H, Huang Q, Liu Q, Guo Y, Lu J, Li X, Xue C, Han Q. Transcriptional Repression of p53 by PAX3 Contributes to Gliomagenesis and Differentiation of Glioma Stem Cells. Front Mol Neurosci 2018; 11:187. [PMID: 29937714 PMCID: PMC6003214 DOI: 10.3389/fnmol.2018.00187] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 05/14/2018] [Indexed: 12/31/2022] Open
Abstract
Although there are available therapies as surgery, chemotherapy and radiation, glioblastoma (GBM) still has been considered as the most common and overwhelming primary tumor of brain. In GBM, the brain glioma stem cells (BGSCs) were identified and played a crucial role in resistance of GBM to conventional therapies described above. PAX3 was previously identified by our group as a diagnostic/prognostic marker and a therapeutic regulator in the therapy of GBM. Here, we hypothesized PAX3/p53 axis promoted the process of differentiation, regulating to the cancer stem cell properties, such as proliferation and migration. The correlation between PAX3 and p53 in GBM were first clarified. Immunofluorescence of p53 was shown activated following BGSCs differentiation. We further identified that PAX3 might specifically bind to the promoter of p53 gene, and transcriptionally repressed p53 expression. ChIP assay further confirmed that PAX3/p53 axis regulated the differentiation process of BGSCs. Then, the function of PAX3 in BGSCs were sequentially investigated in vitro and in vivo. Ectopic PAX3 expression promoted BGSCs growth and migration while PAX3 knockdown suppressed BGSCs growth, migration in vitro and in vivo. Similar to PAX3 overexpression, p53 inhibition also showed increase in growth and migration of differentiated BGSCs. Regarding the functional interaction between PAX3 and p53, PAX3 knockdown-mediated decrease in proliferation was partially rescued by p53 inhibition. Hypoxia significantly promoted the migration potential of BGSCs. In addition, hypoxia inducible factor-1α (HIF-1α) might be a potential upstream regulator of PAX3 in differentiated BGSCs under hypoxia. Our work may provide a supplementary mechanism in regulation of the BGSCs differentiation and their functions, which should provide novel therapeutic targets for GBM in future.
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Affiliation(s)
- Hui Zhu
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China.,Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Hongkui Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Qingfeng Huang
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Qianqian Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yibing Guo
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Jingjing Lu
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiaohong Li
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Chengbin Xue
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China.,Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Qianqian Han
- National Institute for Food and Drug Control, Beijing, China
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Stelcer E, Kulcenty K, Rucinski M, Jopek K, Richter M, Trzeciak T, Suchorska WM. Forced differentiation in vitro leads to stress-induced activation of DNA damage response in hiPSC-derived chondrocyte-like cells. PLoS One 2018; 13:e0198079. [PMID: 29864138 PMCID: PMC5986142 DOI: 10.1371/journal.pone.0198079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 05/14/2018] [Indexed: 01/22/2023] Open
Abstract
A human induced pluripotent stem cell line (GPCCi001-A) created by our group was differentiated towards chondrocyte-like cells (ChiPS) via monolayer culturing with growth factors. ChiPS are promising because they have the potential to be used in tissue engineering to regenerate articular cartilage. However, their safety must be confirmed before they can be routinely used in regenerative medicine. Using microarray analysis, we compared the ChiPS to both GPCCi001-A cells and chondrocytes. The analysis showed that, compared to both GPCCi001-A cells and chondrocytes, the expression of genes engaged in DNA damage and in the tumor protein p53 signalling pathways was significantly higher in the ChiPS. The significant amount of DNA double strand breaks and increased DNA damage response may lead to incomplete DNA repair and the accumulation of mutations and, ultimately, to genetic instability. These findings provide evidence indicating that the differentiation process in vitro places stress on human induced pluripotent stem cells (hiPSCs). The results of this study raise doubts about the use of stem cell-derived components given the negative effects of the differentiation process in vitro on hiPSCs.
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Affiliation(s)
- Ewelina Stelcer
- Radiobiology Laboratory, Greater Poland Cancer Centre, Poznan, Poland
- The Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznan, Poland
- * E-mail:
| | - Katarzyna Kulcenty
- Radiobiology Laboratory, Greater Poland Cancer Centre, Poznan, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznan, Poland
| | - Marcin Rucinski
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Karol Jopek
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Magdalena Richter
- Department of Orthopedics and Traumatology, Poznan University of Medical Sciences, Poznan, Poland
| | - Tomasz Trzeciak
- Department of Orthopedics and Traumatology, Poznan University of Medical Sciences, Poznan, Poland
| | - Wiktoria Maria Suchorska
- Radiobiology Laboratory, Greater Poland Cancer Centre, Poznan, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznan, Poland
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36
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Kaneko S, Li X. X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. SCIENCE ADVANCES 2018; 4:eaar5598. [PMID: 29928692 PMCID: PMC6007159 DOI: 10.1126/sciadv.aar5598] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 04/27/2018] [Indexed: 05/30/2023]
Abstract
Men are much more likely than women to develop bladder cancer (BCa), but the underlying cause of this gender disparity remains poorly defined. Using sex-reversed mice, we show that the sex chromosome complement is an independent cause and, moreover, amplifies the biasing effects of sex hormones. We also show that the X-linked lysine demethylase 6A (KDM6A) is a sexually dimorphic gene. Wild-type but not catalytically dead KDM6A confers sustained tumor suppressor activity in vitro. Knockout of mouse Kdm6a reduces expression of Cdkn1a and Perp, canonical gene targets of the tumor suppressor p53. Consistently, loss of Kdm6a increases BCa risk in female mice, and mutations or reduced expression of human KDM6A predicts poor prognosis of female BCa patients. Collectively, the study reveals that the X chromosome protects against BCa among females via a KDM6A-dependent epigenetic mechanism and further suggests that KDM6A is a prototypical sex-biasing tumor suppressor with both demethylase-dependent and demethylase-independent activities.
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p53-Dependent and -Independent Epithelial Integrity: Beyond miRNAs and Metabolic Fluctuations. Cancers (Basel) 2018; 10:cancers10060162. [PMID: 29799511 PMCID: PMC6024951 DOI: 10.3390/cancers10060162] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 05/22/2018] [Accepted: 05/23/2018] [Indexed: 12/14/2022] Open
Abstract
In addition to its classical roles as a tumor suppressor, p53 has also been shown to act as a guardian of epithelial integrity by inducing the microRNAs that target transcriptional factors driving epithelial⁻mesenchymal transition. On the other hand, the ENCODE project demonstrated an enrichment of putative motifs for the binding of p53 in epithelial-specific enhancers, such as CDH1 (encoding E-cadherin) enhancers although its biological significance remained unknown. Recently, we identified two novel modes of epithelial integrity (i.e., maintenance of CDH1 expression): one involves the binding of p53 to a CDH1 enhancer region and the other does not. In the former, the binding of p53 is necessary to maintain permissive histone modifications around the CDH1 transcription start site, whereas in the latter, p53 does not bind to this region nor affect histone modifications. Furthermore, these mechanisms likely coexisted within the same tissue. Thus, the mechanisms involved in epithelial integrity appear to be much more complex than previously thought. In this review, we describe our findings, which may instigate further experimental scrutiny towards understanding the whole picture of epithelial integrity as well as the related complex asymmetrical functions of p53. Such understanding will be important not only for cancer biology but also for the safety of regenerative medicine.
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Abstract
Most human cancers harbor mutations in the gene encoding p53. As a result, research on p53 in the past few decades has focused primarily on its role as a tumor suppressor. One consequence of this focus is that the functions of p53 in development have largely been ignored. However, recent advances, such as the genomic profiling of embryonic stem cells, have uncovered the significance and mechanisms of p53 functions in mammalian cell differentiation and development. As we review here, these recent findings reveal roles that complement the well-established roles for p53 in tumor suppression.
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Affiliation(s)
- Abhinav K Jain
- Department of Epigenetics and Molecular Carcinogenesis, Center for Stem Cell and Development Biology, Center for Cancer Epigenetics, The University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michelle Craig Barton
- Department of Epigenetics and Molecular Carcinogenesis, Center for Stem Cell and Development Biology, Center for Cancer Epigenetics, The University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Puisieux A, Pommier RM, Morel AP, Lavial F. Cellular Pliancy and the Multistep Process of Tumorigenesis. Cancer Cell 2018; 33:164-172. [PMID: 29438693 DOI: 10.1016/j.ccell.2018.01.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 12/22/2017] [Accepted: 01/11/2018] [Indexed: 12/13/2022]
Abstract
Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.
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Affiliation(s)
- Alain Puisieux
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe labellisée Ligue Contre le Cancer "EMT and Cancer Cell Plasticity", Lyon 69008, France; LabEx DEVweCAN, Université de Lyon, 69000 Lyon, France.
| | - Roxane M Pommier
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe labellisée Ligue Contre le Cancer "EMT and Cancer Cell Plasticity", Lyon 69008, France; LabEx DEVweCAN, Université de Lyon, 69000 Lyon, France
| | - Anne-Pierre Morel
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe labellisée Ligue Contre le Cancer "EMT and Cancer Cell Plasticity", Lyon 69008, France; LabEx DEVweCAN, Université de Lyon, 69000 Lyon, France
| | - Fabrice Lavial
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe "Cellular Reprogramming and Oncogenesis", Lyon 69008, France
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40
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Stewart-Ornstein J, Cheng HWJ, Lahav G. Conservation and Divergence of p53 Oscillation Dynamics across Species. Cell Syst 2017; 5:410-417.e4. [PMID: 29055670 PMCID: PMC5687840 DOI: 10.1016/j.cels.2017.09.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/08/2017] [Accepted: 09/21/2017] [Indexed: 12/24/2022]
Abstract
The tumor-suppressing transcription factor p53 is highly conserved at the protein level and plays a key role in the DNA damage response. One important aspect of p53 regulation is its dynamics in response to DNA damage, which include oscillations. Here, we observe that, while the qualitative oscillatory nature of p53 dynamics is conserved across cell lines derived from human, monkey, dog, mouse, and rat, the oscillation period is variable. Specifically, rodent cells exhibit rapid p53 oscillations, whereas dog, monkey, and human cells show slower oscillations. Computational modeling and experiments identify stronger negative feedback between p53 and MDM2 as the driver of faster oscillations in rodents, suggesting that the period of oscillation is a network-level property. In total, our study shows that despite highly conserved signaling, the quantitative features of p53 oscillations can diverge across evolution. We caution that strong amino acid conservation of proteins and transcriptional network similarity do not necessarily imply conservation of time dynamics.
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Affiliation(s)
| | - Ho Wa Jacky Cheng
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Galit Lahav
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
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Shpargel KB, Starmer J, Wang C, Ge K, Magnuson T. UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome. Proc Natl Acad Sci U S A 2017; 114:E9046-E9055. [PMID: 29073101 PMCID: PMC5664495 DOI: 10.1073/pnas.1705011114] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Kabuki syndrome, a congenital craniofacial disorder, manifests from mutations in an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A) or a H3 lysine 4 methylase (KMT2D). However, the cellular and molecular etiology of histone-modifying enzymes in craniofacial disorders is unknown. We now establish Kabuki syndrome as a neurocristopathy, whereby the majority of clinical features are modeled in mice carrying neural crest (NC) deletion of UTX, including craniofacial dysmorphism, cardiac defects, and postnatal growth retardation. Female UTX NC knockout (FKO) demonstrates enhanced phenotypic severity over males (MKOs), due to partial redundancy with UTY, a Y-chromosome demethylase-dead homolog. Thus, NC cells may require demethylase-independent UTX activity. Consistently, Kabuki causative point mutations upstream of the JmjC domain do not disrupt UTX demethylation. We have isolated primary NC cells at a phenocritical postmigratory timepoint in both FKO and MKO mice, and genome-wide expression and histone profiling have revealed UTX molecular function in establishing appropriate chromatin structure to regulate crucial NC stem-cell signaling pathways. However, the majority of UTX regulated genes do not experience aberrations in H3K27me3 or H3K4me3, implicating alternative roles for UTX in transcriptional control. These findings are substantiated through demethylase-dead knockin mutation of UTX, which supports appropriate facial development.
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Affiliation(s)
- Karl B Shpargel
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7264
| | - Joshua Starmer
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7264
| | - Chaochen Wang
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Kai Ge
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Terry Magnuson
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264;
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7264
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Bao F, LoVerso PR, Fisk JN, Zhurkin VB, Cui F. p53 binding sites in normal and cancer cells are characterized by distinct chromatin context. Cell Cycle 2017; 16:2073-2085. [PMID: 28820292 PMCID: PMC5731425 DOI: 10.1080/15384101.2017.1361064] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The tumor suppressor protein p53 interacts with DNA in a sequence-dependent manner. Thousands of p53 binding sites have been mapped genome-wide in normal and cancer cells. However, the way p53 selectively binds its cognate sites in different types of cells is not fully understood. Here, we performed a comprehensive analysis of 25 published p53 cistromes and identified 3,551 and 6,039 ‘high-confidence’ binding sites in normal and cancer cells, respectively. Our analysis revealed 2 distinct epigenetic features underlying p53-DNA interactions in vivo. First, p53 binding sites are associated with transcriptionally active histone marks (H3K4me3 and H3K36me3) in normal-cell chromatin, but with repressive histone marks (H3K27me3) in cancer-cell chromatin. Second, p53 binding sites in cancer cells are characterized by a lower level of DNA methylation than their counterparts in normal cells, probably related to global hypomethylation in cancers. Intriguingly, regardless of the cell type, p53 sites are highly enriched in the endogenous retroviral elements of the ERV1 family, highlighting the importance of this repeat family in shaping the transcriptional network of p53. Moreover, the p53 sites exhibit an unusual combination of chromatin patterns: high nucleosome occupancy and, at the same time, high sensitivity to DNase I. Our results suggest that p53 can access its target sites in a chromatin environment that is non-permissive to most DNA-binding transcription factors, which may allow p53 to act as a pioneer transcription factor in the context of chromatin.
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Affiliation(s)
- Feifei Bao
- a Thomas H. Gosnell School of Life Sciences , Rochester Institute of Technology , Rochester , NY , USA
| | - Peter R LoVerso
- b Laboratory of Cell Biology , National Cancer Institute , Bethesda , MD , USA
| | - Jeffrey N Fisk
- a Thomas H. Gosnell School of Life Sciences , Rochester Institute of Technology , Rochester , NY , USA
| | - Victor B Zhurkin
- b Laboratory of Cell Biology , National Cancer Institute , Bethesda , MD , USA
| | - Feng Cui
- a Thomas H. Gosnell School of Life Sciences , Rochester Institute of Technology , Rochester , NY , USA
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She S, Wei Q, Kang B, Wang YJ. Cell cycle and pluripotency: Convergence on octamer‑binding transcription factor 4 (Review). Mol Med Rep 2017; 16:6459-6466. [PMID: 28901500 PMCID: PMC5865814 DOI: 10.3892/mmr.2017.7489] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Accepted: 07/14/2017] [Indexed: 12/14/2022] Open
Abstract
Embryonic stem cells (ESCs) have unlimited expansion potential and the ability to differentiate into all somatic cell types for regenerative medicine and disease model studies. Octamer-binding transcription factor 4 (OCT4), encoded by the POU domain, class 5, transcription factor 1 gene, is a transcription factor vital for maintaining ESC pluripotency and somatic reprogramming. Many studies have established that the cell cycle of ESCs is featured with an abbreviated G1 phase and a prolonged S phase. Changes in cell cycle dynamics are intimately associated with the state of ESC pluripotency, and manipulating cell-cycle regulators could enable a controlled differentiation of ESCs. The present review focused primarily on the emerging roles of OCT4 in coordinating the cell cycle progression, the maintenance of pluripotency and the glycolytic metabolism in ESCs.
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Affiliation(s)
- Shiqi She
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Qucheng Wei
- Cardiovascular Key Lab of Zhejiang, Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Bo Kang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Ying-Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Jain AK, Xi Y, McCarthy R, Allton K, Akdemir KC, Patel LR, Aronow B, Lin C, Li W, Yang L, Barton MC. LncPRESS1 Is a p53-Regulated LncRNA that Safeguards Pluripotency by Disrupting SIRT6-Mediated De-acetylation of Histone H3K56. Mol Cell 2017; 64:967-981. [PMID: 27912097 DOI: 10.1016/j.molcel.2016.10.039] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/07/2016] [Accepted: 10/28/2016] [Indexed: 12/12/2022]
Abstract
Recent evidence suggests that lncRNAs play an integral regulatory role in numerous functions, including determination of cellular identity. We determined global expression (RNA-seq) and genome-wide profiles (ChIP-seq) of histone post-translational modifications and p53 binding in human embryonic stem cells (hESCs) undergoing differentiation to define a high-confidence set of 40 lncRNAs, which are p53 transcriptional targets. We focused on lncRNAs highly expressed in pluripotent hESCs and repressed by p53 during differentiation to identify lncPRESS1 as a p53-regulated transcript that maintains hESC pluripotency in concert with core pluripotency factors. RNA-seq of hESCs depleted of lncPRESS1 revealed that lncPRESS1 controls a gene network that promotes pluripotency. Further, we found that lncPRESS1 physically interacts with SIRT6 and prevents SIRT6 chromatin localization, which maintains high levels of histone H3K56 and H3K9 acetylation at promoters of pluripotency genes. In summary, we describe a p53-regulated, pluripotency-specific lncRNA that safeguards the hESC state by disrupting SIRT6 activity.
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Affiliation(s)
- Abhinav K Jain
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Stem Cell and Development Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Yuanxin Xi
- Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ryan McCarthy
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Stem Cell and Development Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kendra Allton
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Stem Cell and Development Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kadir C Akdemir
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lalit R Patel
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - Bruce Aronow
- Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Chunru Lin
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wei Li
- Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Liuqing Yang
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michelle C Barton
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Stem Cell and Development Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
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Zou M, Toivanen R, Mitrofanova A, Floch N, Hayati S, Sun Y, Le Magnen C, Chester D, Mostaghel EA, Califano A, Rubin MA, Shen MM, Abate-Shen C. Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer. Cancer Discov 2017; 7:736-749. [PMID: 28411207 PMCID: PMC5501744 DOI: 10.1158/2159-8290.cd-16-1174] [Citation(s) in RCA: 288] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 11/14/2016] [Accepted: 04/12/2017] [Indexed: 11/16/2022]
Abstract
Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.Significance: Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. Cancer Discov; 7(7); 736-49. ©2017 AACR.See related commentary by Sinha and Nelson, p. 673This article is highlighted in the In This Issue feature, p. 653.
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Affiliation(s)
- Min Zou
- Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Roxanne Toivanen
- Departments of Medicine and Genetics and Developmental Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Antonina Mitrofanova
- Department of Systems Biology, Columbia University Medical Center, New York, New York; and Department of Health Informatics, Rutgers, The State University of New Jersey, Newark, New Jersey
| | - Nicolas Floch
- Department of Urology, Columbia University Medical Center, New York, New York
| | - Sheida Hayati
- Department of Health Informatics, Rutgers, The State University of New Jersey, Newark, New Jersey
| | - Yanping Sun
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - Clémentine Le Magnen
- Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Daniel Chester
- Department of Urology, Columbia University Medical Center, New York, New York
| | - Elahe A Mostaghel
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Andrea Califano
- Departments of Systems Biology, Biomedical Informatics, and Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Mark A Rubin
- Englander Institute for Precision Medicine and Department of Pathology and Laboratory Medicine, Weil Cornell Medical College and New York-Presbyterian Hospital, New York, New York
| | - Michael M Shen
- Departments of Medicine, Genetics and Development, Urology, and Systems Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
| | - Cory Abate-Shen
- Departments of Urology, Medicine, Systems Biology, and Pathology and Cell Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
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46
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Suchorska WM, Augustyniak E, Łukjanow M. Comparison of the early response of human embryonic stem cells and human induced pluripotent stem cells to ionizing radiation. Mol Med Rep 2017; 15:1952-1962. [PMID: 28259963 PMCID: PMC5364988 DOI: 10.3892/mmr.2017.6270] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 01/09/2017] [Indexed: 12/14/2022] Open
Abstract
Despite the well-demonstrated efficacy of stem cell (SC) therapy, this approach has a number of key drawbacks. One important concern is the response of pluripotent SCs to treatment with ionizing radiation (IR), given that SCs used in regenerative medicine will eventually be exposed to IR for diagnostic or treatment-associated purposes. Therefore, the aim of the present study was to examine and compare early IR-induced responses of pluripotent SCs to assess their radioresistance and radiosensitivity. In the present study, 3 cell lines; human embryonic SCs (hESCs), human induced pluripotent SCs (hiPSCs) and primary human dermal fibroblasts (PHDFs); were exposed to IR at doses ranging from 0 to 15 gray (Gy). Double strand breaks (DSBs), and the gene expression of the following DNA repair genes were analyzed: P53; RAD51; BRCA2; PRKDC; and XRCC4. hiPSCs demonstrated greater radioresistance, as fewer DSBs were identified, compared with hESCs. Both pluripotent SC lines exhibited distinct gene expression profiles in the most common DNA repair genes that are involved in homologous recombination, non-homologous end-joining and enhanced DNA damage response following IR exposure. Although hESCs and hiPSCs are equivalent in terms of capacity for pluripotency and differentiation into 3 germ layers, the results of the present study indicate that these 2 types of SCs differ in gene expression following exposure to IR. Consequently, further research is required to determine whether hiPSCs and hESCs are equally safe for application in clinical practice. The present study contributes to a greater understanding of DNA damage response (DDR) mechanisms activated in pluripotent SCs and may aid in the future development of safe SC-based clinical protocols.
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Affiliation(s)
| | - Ewelina Augustyniak
- Radiobiology Laboratory, Greater Poland Cancer Centre, 61‑866 Poznan, Poland
| | - Magdalena Łukjanow
- Radiobiology Laboratory, Greater Poland Cancer Centre, 61‑866 Poznan, Poland
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47
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TRIM28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation. Oncogene 2017; 36:2991-3001. [PMID: 28068325 DOI: 10.1038/onc.2016.453] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 08/11/2016] [Accepted: 10/03/2016] [Indexed: 02/07/2023]
Abstract
Histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) is generally associated with H3K27 methylation and gene silencing, as a member of the polycomb repressor 2 (PRC2) complex. Immunoprecipitation and mass spectrometry of the EZH2-protein interactome in estrogen receptor positive, breast cancer-derived MCF7 cells revealed EZH2 interactions with subunits of chromatin remodeler SWI/SNF complex and TRIM28, which formed a complex with EZH2 distinct from PRC2. Unexpectedly, transcriptome profiling showed that EZH2 primarily activates, rather than represses, transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients. TRIM28 depletion repressed EZH2 recruitment to chromatin and expression of this gene set, in parallel with decreased CD44hi/CD24lo mammosphere formation. Mammosphere formation, inhibited by EZH2 depletion, was rescued by ectopic expression of EZH2 but not by TRIM28 expression or by EZH2 mutated at the region (pre-SET domain) of TRIM28 interaction. These results support PRC2-independent functions of EZH2 and TRIM28 in activation of gene expression that promotes mammary stem cell enrichment and maintenance.
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48
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49
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Gil VS, Bhagat G, Howell L, Zhang J, Kim CH, Stengel S, Vega F, Zelent A, Petrie K. Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice. Dis Model Mech 2016; 9:1483-1495. [PMID: 27799148 PMCID: PMC5200892 DOI: 10.1242/dmm.023366] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 10/21/2016] [Indexed: 12/11/2022] Open
Abstract
Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors. Summary: This study demonstrates that aberrant expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma through altering expression of genes involved in the cell cycle and survival, and modulating the activity of key B-lineage factors such as BCL6 and p53.
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Affiliation(s)
- Veronica S Gil
- Division of Clinical Studies, Institute of Cancer Research, London SM2 5NG, UK
| | - Govind Bhagat
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.,Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Louise Howell
- Division of Molecular Pathology, Institute of Cancer Research, London SM2 5NG, UK
| | - Jiyuan Zhang
- Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.,Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
| | - Chae H Kim
- Division of Hematopathology, Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Sven Stengel
- Division of Molecular Pathology, Institute of Cancer Research, London SM2 5NG, UK
| | - Francisco Vega
- Division of Hematopathology, Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Arthur Zelent
- Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Kevin Petrie
- Department of Biological and Environmental Sciences, Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK
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50
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Suvorova II, Grigorash BB, Chuykin IA, Pospelova TV, Pospelov VA. G1 checkpoint is compromised in mouse ESCs due to functional uncoupling of p53-p21Waf1 signaling. Cell Cycle 2016; 15:52-63. [PMID: 26636245 DOI: 10.1080/15384101.2015.1120927] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Mouse embryonic stem cells (mESCs) lack of G1 checkpoint despite that irradiation (IR) activates ATM/ATR-mediated DDR signaling pathway. The IR-induced p53 localizes in the nuclei and up-regulates p21/Waf1 transcription but that does not lead to accumulation of p21/Waf1 protein. The negative control of the p21Waf1 expression appears to occur at 2 levels of regulation. First, both p21/Waf1 gene transcription and the p21/Waf1 protein content increase in mESCs treated with histone-deacetylase inhibitors, implying its epigenetic regulation. Second, proteasome inhibitors cause the p21/Waf1 accumulation, indicating that the protein is a subject of proteasome-dependent degradation in ESСs. Then, the dynamics of IR-induced p21Waf1 protein show its accumulation at long-term time points (3 and 5 days) that coincides with an increase in the proportion of G1-phase cells, down-regulation of Oct4 and Nanog pluripotent gene transcription and activation of endoderm-specific genes sox17 and afp. In addition, nutlin-dependent stabilization of p53 in mESC was also accompanied by the accumulation of p21/Waf1 as well as restoration of G1 checkpoint and an onset of differentiation. Thus, the lack of functional p21/Waf1 is indispensable for maintaining self-renewal and pluripotency of mESCs.
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Affiliation(s)
- Irina I Suvorova
- a Institute of Cytology , Russian Academy of Sciences , St-Petersburg , Russia.,b Saint-Petersburg State University, Saint-Petersburg State University , St-Petersburg , Russia
| | - Bogdan B Grigorash
- a Institute of Cytology , Russian Academy of Sciences , St-Petersburg , Russia.,b Saint-Petersburg State University, Saint-Petersburg State University , St-Petersburg , Russia
| | | | - Tatiana V Pospelova
- a Institute of Cytology , Russian Academy of Sciences , St-Petersburg , Russia.,b Saint-Petersburg State University, Saint-Petersburg State University , St-Petersburg , Russia
| | - Valery A Pospelov
- a Institute of Cytology , Russian Academy of Sciences , St-Petersburg , Russia.,b Saint-Petersburg State University, Saint-Petersburg State University , St-Petersburg , Russia
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