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dc.contributor.authorKwan, Suet-Yan
dc.contributor.authorSheel, Ankur
dc.contributor.authorSong, Chun-Qing
dc.contributor.authorZhang, Xiao-Ou
dc.contributor.authorJiang, Tingting
dc.contributor.authorDang, Hien
dc.contributor.authorCao, Yueying
dc.contributor.authorOzata, Deniz M
dc.contributor.authorMou, Haiwei
dc.contributor.authorYin, Hao
dc.contributor.authorWeng, Zhiping
dc.contributor.authorWang, Xin Wei
dc.contributor.authorXue, Wen
dc.date2022-08-11T08:10:17.000
dc.date.accessioned2022-08-23T17:03:12Z
dc.date.available2022-08-23T17:03:12Z
dc.date.issued2019-06-12
dc.date.submitted2019-07-08
dc.identifier.citation<p>Hepatology. 2019 Jun 12. doi: 10.1002/hep.30807. [Epub ahead of print] <a href="https://doi.org/10.1002/hep.30807">Link to article on publisher's site</a></p>
dc.identifier.issn0270-9139 (Linking)
dc.identifier.doi10.1002/hep.30807
dc.identifier.pmid31188495
dc.identifier.urihttp://hdl.handle.net/20.500.14038/44376
dc.description.abstractHepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments and the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Using a kinome CRISPR screen in three human HCC cell lines, we identified transformation/transcription domain-associated protein (TRRAP) as an essential gene for HCC cell proliferation. TRRAP has been implicated in oncogenic transformation, but how it functions in cancer cell proliferation is not established. Here, we show that depletion of TRRAP or its co-factor, histone acetyltransferase KAT5, inhibits HCC cell growth via induction of p53- and p21-independent senescence. Integrated cancer genomics analyses using patient data and RNA-sequencing identified mitotic genes as key TRRAP/KAT5 targets in HCC, and subsequent cell cycle analyses revealed that TRRAP- and KAT5-depleted cells are arrested at G2/M phase. Depletion of TOP2A, a mitotic gene and TRRAP/KAT5 target, was sufficient to recapitulate the senescent phenotype of TRRAP/KAT5 knockdown. CONCLUSION: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation via activation of mitotic genes. Targeting the TRRAP/KAT5 complex is a potential therapeutic strategy for HCC.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31188495&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsThis is the peer reviewed version of the following article: Kwan S. et al. (2019), Depletion of TRRAP induces p53‐independent senescence in liver cancer by downregulating mitotic genes. Hepatology. doi:10.1002/hep.30807, which has been published in final form at https://doi.org/10.1002/hep.30807. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Accepted manuscript published after 12 months as allowed by publisher's self-archiving policy at https://authorservices.wiley.com/author-resources/Journal-Authors/licensing/self-archiving.html.
dc.subjectCRISPR screen
dc.subjectG2/M arrest
dc.subjectHepatocellular carcinoma
dc.subjecthistone acetyltransferase
dc.subjectsenescence
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCancer Biology
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectDigestive System Diseases
dc.subjectHepatology
dc.subjectNeoplasms
dc.titleDepletion of TRRAP induces p53-independent senescence in liver cancer by downregulating mitotic genes
dc.typeAccepted Manuscript
dc.source.journaltitleHepatology (Baltimore, Md.)
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1103&amp;context=pmm_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/pmm_pp/104
dc.legacy.embargo2020-06-12T00:00:00-07:00
dc.identifier.contextkey14880295
refterms.dateFOA2022-08-23T17:03:13Z
html.description.abstract<p>Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments and the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Using a kinome CRISPR screen in three human HCC cell lines, we identified transformation/transcription domain-associated protein (TRRAP) as an essential gene for HCC cell proliferation. TRRAP has been implicated in oncogenic transformation, but how it functions in cancer cell proliferation is not established. Here, we show that depletion of TRRAP or its co-factor, histone acetyltransferase KAT5, inhibits HCC cell growth via induction of p53- and p21-independent senescence. Integrated cancer genomics analyses using patient data and RNA-sequencing identified mitotic genes as key TRRAP/KAT5 targets in HCC, and subsequent cell cycle analyses revealed that TRRAP- and KAT5-depleted cells are arrested at G2/M phase. Depletion of TOP2A, a mitotic gene and TRRAP/KAT5 target, was sufficient to recapitulate the senescent phenotype of TRRAP/KAT5 knockdown. CONCLUSION: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation via activation of mitotic genes. Targeting the TRRAP/KAT5 complex is a potential therapeutic strategy for HCC.</p>
dc.identifier.submissionpathpmm_pp/104
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentLi Weibo Institute for Rare Diseases Research
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.contributor.departmentRNA Therapeutics Institute


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