Abstract
Monomethylation of histone H3 lysine 4 (H3K4me1) is enriched at enhancers that are primed for activation and the levels of this histone mark are frequently altered in various human cancers. Yet, how alterations in H3K4me1 are established and the consequences of these epigenetic changes in tumorigenesis are not well understood. Using ChIP-Seq in human colon cancer cells, we demonstrate that mutant p53 depletion results in decreased H3K4me1 levels at active enhancers that reveal a striking colocalization of mutant p53 and the H3K4 monomethyltransferase MLL4 following chronic tumor necrosis factor alpha (TNF) signaling. We further reveal that mutant p53 forms physiological associations and direct interactions with MLL4 and promotes the enhancer binding of MLL4, which is required for TNF-inducible H3K4me1 and histone H3 lysine 27 acetylation (H3K27ac) levels, enhancer-derived transcript (eRNA) synthesis, and mutant p53-dependent target gene activation. Complementary in vitro studies with recombinant chromatin and purified proteins demonstrate that binding of the MLL3/4 complex and H3K4me1 deposition is enhanced by mutant p53 and p300-mediated acetylation, which in turn reflects a MLL3/4-dependent enhancement of mutant p53 and p300-dependent transcriptional activation. Collectively, our findings establish a mechanism in which mutant p53 cooperates with MLL4 to regulate aberrant enhancer activity and tumor-promoting gene expression in response to chronic immune signaling.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 13234-13246 |
| Number of pages | 13 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 34 |
| DOIs | |
| State | Published - Aug 24 2018 |
Funding
This work was supported by the Sidney Kimmel Foundation for Cancer Research, Research Scholar Award 857A6A, and University of California Cancer Research Coordinating Committee Award CRN-17-420616 (to S. M. L.) and by the UCSD Cellular and Molecular Genetics Training Pro-gram through the National Institute of General Medical Sciences Institu-tional Grant T32 GM007240 (to H.R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by the Sidney Kimmel Foundation for Cancer Research, Research Scholar Award 857A6A, and University of California Cancer Research Coordinating Committee Award CRN-17-420616 (to S. M. L.) and by the UCSD Cellular and Molecular Genetics Training Program through the National Institute of General Medical Sciences Institutional Grant T32 GM007240 (to H.R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are grateful to Kai Ge (National Institutes of Health) for providing the HeLa cells that stably express FLAG-PA1 as well as MLL3 and MLL4 antibodies, Robert Roeder (Rockefeller University) for providing the UTX and PTIP antibodies, and Xinbin Chen (UC Davis) for providing the SW480 shLacZ and shp53 cell lines. We also thank Danielle Freeman for technical support.
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry
- Cell Biology
