MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer Journal Article

Authors: Zhu, C.; Soto-Feliciano, Y. M.; Morris, J. P.; Huang, C. H.; Koche, R. P.; Ho, Y. J.; Banito, A.; Chen, C. W.; Shroff, A.; Tian, S.; Livshits, G.; Chen, C. C.; Fennell, M.; Armstrong, S. A.; Allis, C. D.; Tschaharganeh, D. F.; Lowe, S. W.
Article Title: MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer
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. © 2023, eLife Sciences Publications Ltd. All rights reserved.
Keywords: genetics; liver cell carcinoma; carcinoma, hepatocellular; liver neoplasms; mouse; animal; metabolism; animals; mice; pathology; carcinogenesis; chromatin; liver tumor; cyclin dependent kinase inhibitor 2a; cyclin-dependent kinase inhibitor p16; tumor suppressor protein p14arf; humans; human; cdkn2a protein, human
Journal Title: eLife
Volume: 12
ISSN: 2050-084X
Publisher: eLife Sciences Publications Ltd.  
Date Published: 2023-06-01
Start Page: e80854
Language: English
DOI: 10.7554/eLife.80854
PUBMED: 37261974
PROVIDER: scopus
PMCID: PMC10279454
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Scott W Lowe -- Source: Scopus
Citation Impact
MSK Authors
  1. Scott W Lowe
    234 Lowe
  2. Aditya Shishir Shroff
    3 Shroff
  3. Sha Tian
    11 Tian
  4. Chun-Wei Chen
    20 Chen
  5. Myles Ashley Fennell
    22 Fennell
  6. Richard Patrick Koche
    146 Koche
  7. Chun-Hao   Huang
    24 Huang
  8. Chi-Chao   Chen
    18 Chen
  9. Yu-jui Ho
    35 Ho
  10. Changyu Zhu
    9 Zhu