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@ARTICLE{Zhu:276949,
      author       = {C. Zhu and Y. M. Soto-Feliciano and J. P. Morris and C.-H.
                      Huang and R. P. Koche and Y.-J. Ho and A. Banito and C.-W.
                      Chen and A. Shroff and S. Tian and G. Livshits and C.-C.
                      Chen and M. Fennell and S. A. Armstrong and C. D. Allis and
                      D. F. Tschaharganeh$^*$ and S. W. Lowe},
      title        = {{MLL}3 regulates the {CDKN}2{A} tumor suppressor locus in
                      liver cancer.},
      journal      = {eLife},
      volume       = {12},
      issn         = {2050-084X},
      address      = {Cambridge},
      publisher    = {eLife Sciences Publications},
      reportid     = {DKFZ-2023-01226},
      pages        = {e80854},
      year         = {2023},
      abstract     = {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.},
      keywords     = {Humans / Animals / Mice / Liver Neoplasms: genetics / Liver
                      Neoplasms: pathology / Tumor Suppressor Protein p14ARF:
                      genetics / Carcinoma, Hepatocellular: genetics / Carcinoma,
                      Hepatocellular: pathology / Cyclin-Dependent Kinase
                      Inhibitor p16: genetics / Cyclin-Dependent Kinase Inhibitor
                      p16: metabolism / Chromatin / Carcinogenesis / MLL3 (Other)
                      / cancer (Other) / cancer biology (Other) / chromatin
                      (Other) / human (Other) / liver cancer (Other) / mouse
                      (Other) / tumor suppressor (Other) / Tumor Suppressor
                      Protein p14ARF (NLM Chemicals) / Cyclin-Dependent Kinase
                      Inhibitor p16 (NLM Chemicals) / Chromatin (NLM Chemicals) /
                      CDKN2A protein, human (NLM Chemicals)},
      cin          = {F190},
      ddc          = {600},
      cid          = {I:(DE-He78)F190-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37261974},
      pmc          = {pmc:PMC10279454},
      doi          = {10.7554/eLife.80854},
      url          = {https://inrepo02.dkfz.de/record/276949},
}