000276949 001__ 276949
000276949 005__ 20240229155008.0
000276949 0247_ $$2doi$$a10.7554/eLife.80854
000276949 0247_ $$2pmid$$apmid:37261974
000276949 0247_ $$2pmc$$apmc:PMC10279454
000276949 0247_ $$2altmetric$$aaltmetric:149305596
000276949 037__ $$aDKFZ-2023-01226
000276949 041__ $$aEnglish
000276949 082__ $$a600
000276949 1001_ $$00000-0003-3583-3638$$aZhu, Changyu$$b0
000276949 245__ $$aMLL3 regulates the CDKN2A tumor suppressor locus in liver cancer.
000276949 260__ $$aCambridge$$beLife Sciences Publications$$c2023
000276949 3367_ $$2DRIVER$$aarticle
000276949 3367_ $$2DataCite$$aOutput Types/Journal article
000276949 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1687357102_6280
000276949 3367_ $$2BibTeX$$aARTICLE
000276949 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000276949 3367_ $$00$$2EndNote$$aJournal Article
000276949 520__ $$aMutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded by KMT2C) histone methyltransferase occur in a range of solid tumors, and heterozygous deletions encompassing KMT2C occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here, we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Kmt2c cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded tumor suppressors p16/Ink4a and p19/Arf. Conversely, elevated KMT2C expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Kmt2c restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in KMT2C and CDKN2A were associated with similar transcriptional profiles in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.
000276949 536__ $$0G:(DE-HGF)POF4-316$$a316 - Infektionen, Entzündung und Krebs (POF4-316)$$cPOF4-316$$fPOF IV$$x0
000276949 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000276949 650_7 $$2Other$$aMLL3
000276949 650_7 $$2Other$$acancer
000276949 650_7 $$2Other$$acancer biology
000276949 650_7 $$2Other$$achromatin
000276949 650_7 $$2Other$$ahuman
000276949 650_7 $$2Other$$aliver cancer
000276949 650_7 $$2Other$$amouse
000276949 650_7 $$2Other$$atumor suppressor
000276949 650_7 $$2NLM Chemicals$$aTumor Suppressor Protein p14ARF
000276949 650_7 $$2NLM Chemicals$$aCyclin-Dependent Kinase Inhibitor p16
000276949 650_7 $$2NLM Chemicals$$aChromatin
000276949 650_7 $$2NLM Chemicals$$aCDKN2A protein, human
000276949 650_2 $$2MeSH$$aHumans
000276949 650_2 $$2MeSH$$aAnimals
000276949 650_2 $$2MeSH$$aMice
000276949 650_2 $$2MeSH$$aLiver Neoplasms: genetics
000276949 650_2 $$2MeSH$$aLiver Neoplasms: pathology
000276949 650_2 $$2MeSH$$aTumor Suppressor Protein p14ARF: genetics
000276949 650_2 $$2MeSH$$aCarcinoma, Hepatocellular: genetics
000276949 650_2 $$2MeSH$$aCarcinoma, Hepatocellular: pathology
000276949 650_2 $$2MeSH$$aCyclin-Dependent Kinase Inhibitor p16: genetics
000276949 650_2 $$2MeSH$$aCyclin-Dependent Kinase Inhibitor p16: metabolism
000276949 650_2 $$2MeSH$$aChromatin
000276949 650_2 $$2MeSH$$aCarcinogenesis
000276949 7001_ $$00000-0002-8523-7917$$aSoto-Feliciano, Yadira M$$b1
000276949 7001_ $$aMorris, John P$$b2
000276949 7001_ $$aHuang, Chun-Hao$$b3
000276949 7001_ $$00000-0002-6820-5083$$aKoche, Richard P$$b4
000276949 7001_ $$aHo, Yu-Jui$$b5
000276949 7001_ $$aBanito, Ana$$b6
000276949 7001_ $$aChen, Chun-Wei$$b7
000276949 7001_ $$aShroff, Aditya$$b8
000276949 7001_ $$aTian, Sha$$b9
000276949 7001_ $$aLivshits, Geulah$$b10
000276949 7001_ $$aChen, Chi-Chao$$b11
000276949 7001_ $$aFennell, Myles$$b12
000276949 7001_ $$00000-0002-9099-4728$$aArmstrong, Scott A$$b13
000276949 7001_ $$aAllis, C David$$b14
000276949 7001_ $$0P:(DE-He78)ceccc9aed8c6e89c00795bce1f1d83a3$$aTschaharganeh, Darjus F$$b15$$udkfz
000276949 7001_ $$00000-0002-5284-9650$$aLowe, Scott W$$b16
000276949 773__ $$0PERI:(DE-600)2687154-3$$a10.7554/eLife.80854$$gVol. 12, p. e80854$$pe80854$$teLife$$v12$$x2050-084X$$y2023
000276949 909CO $$ooai:inrepo02.dkfz.de:276949$$pVDB
000276949 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)ceccc9aed8c6e89c00795bce1f1d83a3$$aDeutsches Krebsforschungszentrum$$b15$$kDKFZ
000276949 9131_ $$0G:(DE-HGF)POF4-316$$1G:(DE-HGF)POF4-310$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lKrebsforschung$$vInfektionen, Entzündung und Krebs$$x0
000276949 9141_ $$y2023
000276949 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2022-09-23T12:20:44Z
000276949 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2022-09-23T12:20:44Z
000276949 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2022-11-23
000276949 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2022-11-23
000276949 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2022-11-23
000276949 915__ $$0StatID:(DE-HGF)0561$$2StatID$$aArticle Processing Charges$$d2022-11-23
000276949 915__ $$0StatID:(DE-HGF)0700$$2StatID$$aFees$$d2022-11-23
000276949 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bELIFE : 2022$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)0320$$2StatID$$aDBCoverage$$bPubMed Central$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Anonymous peer review$$d2022-09-23T12:20:44Z
000276949 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)1040$$2StatID$$aDBCoverage$$bZoological Record$$d2023-08-22
000276949 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bELIFE : 2022$$d2023-08-22
000276949 9201_ $$0I:(DE-He78)F190-20160331$$kF190$$lF190 NWG Cell Plasticity and Epigenetic Remodeling$$x0
000276949 980__ $$ajournal
000276949 980__ $$aVDB
000276949 980__ $$aI:(DE-He78)F190-20160331
000276949 980__ $$aUNRESTRICTED