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| 001 | 276949 | ||
| 005 | 20240229155008.0 | ||
| 024 | 7 | _ | |a 10.7554/eLife.80854 |2 doi |
| 024 | 7 | _ | |a pmid:37261974 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC10279454 |2 pmc |
| 024 | 7 | _ | |a altmetric:149305596 |2 altmetric |
| 037 | _ | _ | |a DKFZ-2023-01226 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 600 |
| 100 | 1 | _ | |a Zhu, Changyu |0 0000-0003-3583-3638 |b 0 |
| 245 | _ | _ | |a MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer. |
| 260 | _ | _ | |a Cambridge |c 2023 |b eLife Sciences Publications |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1687357102_6280 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a Mutations 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. |
| 536 | _ | _ | |a 316 - Infektionen, Entzündung und Krebs (POF4-316) |0 G:(DE-HGF)POF4-316 |c POF4-316 |f POF IV |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de |
| 650 | _ | 7 | |a MLL3 |2 Other |
| 650 | _ | 7 | |a cancer |2 Other |
| 650 | _ | 7 | |a cancer biology |2 Other |
| 650 | _ | 7 | |a chromatin |2 Other |
| 650 | _ | 7 | |a human |2 Other |
| 650 | _ | 7 | |a liver cancer |2 Other |
| 650 | _ | 7 | |a mouse |2 Other |
| 650 | _ | 7 | |a tumor suppressor |2 Other |
| 650 | _ | 7 | |a Tumor Suppressor Protein p14ARF |2 NLM Chemicals |
| 650 | _ | 7 | |a Cyclin-Dependent Kinase Inhibitor p16 |2 NLM Chemicals |
| 650 | _ | 7 | |a Chromatin |2 NLM Chemicals |
| 650 | _ | 7 | |a CDKN2A protein, human |2 NLM Chemicals |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Animals |2 MeSH |
| 650 | _ | 2 | |a Mice |2 MeSH |
| 650 | _ | 2 | |a Liver Neoplasms: genetics |2 MeSH |
| 650 | _ | 2 | |a Liver Neoplasms: pathology |2 MeSH |
| 650 | _ | 2 | |a Tumor Suppressor Protein p14ARF: genetics |2 MeSH |
| 650 | _ | 2 | |a Carcinoma, Hepatocellular: genetics |2 MeSH |
| 650 | _ | 2 | |a Carcinoma, Hepatocellular: pathology |2 MeSH |
| 650 | _ | 2 | |a Cyclin-Dependent Kinase Inhibitor p16: genetics |2 MeSH |
| 650 | _ | 2 | |a Cyclin-Dependent Kinase Inhibitor p16: metabolism |2 MeSH |
| 650 | _ | 2 | |a Chromatin |2 MeSH |
| 650 | _ | 2 | |a Carcinogenesis |2 MeSH |
| 700 | 1 | _ | |a Soto-Feliciano, Yadira M |0 0000-0002-8523-7917 |b 1 |
| 700 | 1 | _ | |a Morris, John P |b 2 |
| 700 | 1 | _ | |a Huang, Chun-Hao |b 3 |
| 700 | 1 | _ | |a Koche, Richard P |0 0000-0002-6820-5083 |b 4 |
| 700 | 1 | _ | |a Ho, Yu-Jui |b 5 |
| 700 | 1 | _ | |a Banito, Ana |b 6 |
| 700 | 1 | _ | |a Chen, Chun-Wei |b 7 |
| 700 | 1 | _ | |a Shroff, Aditya |b 8 |
| 700 | 1 | _ | |a Tian, Sha |b 9 |
| 700 | 1 | _ | |a Livshits, Geulah |b 10 |
| 700 | 1 | _ | |a Chen, Chi-Chao |b 11 |
| 700 | 1 | _ | |a Fennell, Myles |b 12 |
| 700 | 1 | _ | |a Armstrong, Scott A |0 0000-0002-9099-4728 |b 13 |
| 700 | 1 | _ | |a Allis, C David |b 14 |
| 700 | 1 | _ | |a Tschaharganeh, Darjus F |0 P:(DE-He78)ceccc9aed8c6e89c00795bce1f1d83a3 |b 15 |u dkfz |
| 700 | 1 | _ | |a Lowe, Scott W |0 0000-0002-5284-9650 |b 16 |
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| 910 | 1 | _ | |a Deutsches Krebsforschungszentrum |0 I:(DE-588b)2036810-0 |k DKFZ |b 15 |6 P:(DE-He78)ceccc9aed8c6e89c00795bce1f1d83a3 |
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