MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer
- Memorial Sloan Kettering Cancer Center, United States
- Massachusetts Institute of Technology, United States
- The University of North Carolina at Chapel Hill, United States
- Dana-Farber Cancer Institute, United States
- The Rockefeller University, United States
- German Cancer Research Center, Germany
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.
Data availability
Source files of all original gels and Western Blots were provided for the following figures:Figure 1-figure supplement 2B;Figure 4-figure supplement 1A, C, D, E;Figure 5-figure supplement 2B, F, G.RNA sequencing and ChIP sequencing data files that support the findings of this study have been deposited in the Gene Expression Omnibus under the accession code GSE85055, as well as in the Dryad digital repository (doi:10.5061/dryad.7pvmcvdwm; doi:10.5061/dryad.f1vhhmh0h).All other data supporting the findings of this study will be made available upon reasonable request to the corresponding authors.
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Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locusNCBI Gene Expression Omnibus, GSE85055.
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Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locusDryad Digital Repository, doi:10.5061/dryad.7pvmcvdwm.
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MLL3 ChIP sequencing in murine and human HCC cellsDryad Digital Repository, doi:10.5061/dryad.f1vhhmh0h.
Article and author information
Author details
Yadira M Soto-Feliciano
Chun-Wei (David) Chen
Funding
National Cancer Institute (P01 CA013106)
- Scott W Lowe
National Cancer Institute (R01 CA233944)
- Scott W Lowe
National Institute of General Medical Sciences (1K99GM140265-01)
- Yadira M Soto-Feliciano
National Cancer Institute (1F32CA257103)
- Changyu Zhu
American Cancer Society (PF-14-066-01-TBE)
- John P Morris 4th
Helmholtz foundation (VH-NG-1114)
- Darjus F Tschaharganeh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hao Zhu, University of Texas Southwestern Medical Center, United States
Ethics
Animal experimentation: All animal experiments were approved by the MSKCC Institutional Animal Care and Use Committee (protocol 11-06-011). Animals were monitored for signs of ill-health by veterinary staff at the Research Animal Resource Center (RARC) at MSKCC and efforts were made to minimize suffering.
Version history
- Received: June 7, 2022
- Preprint posted: June 9, 2022 (view preprint)
- Accepted: May 31, 2023
- Accepted Manuscript published: June 1, 2023 (version 1)
- Version of Record published: June 19, 2023 (version 2)
Copyright
© 2023, Zhu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer
eLife 12:e80854.
https://doi.org/10.7554/eLife.80854
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