MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53

Abstract

SUMMARY The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of line-age-specific genes, independent of p53.

Outside the p53 RING: Transcription Regulation by Chromatin-Bound MDM2

“…Further profiling of MDM2-dependent gene expression and histone-PTMs in p53 À/À colon cancerderived cells revealed that loss of MDM2 caused significant reductions in H3K27me3 and H2AK119ub1 at PRC2-target genes. Taken together, Wienken et al (2016) show that a major activity of MDM2 consists of governing a subset of PRC2-regulated genes by promoting positive feedback between H3K27me3 and H2AK119ub1 in tumor cells as well as stem cells ( Figure 1). Thus, aberrant expression of MDM2 in cancer cells not only counteracts p53-mediated inhibition of cell proliferation, but also maintains a stem cell phenotype, which helps explain why cancer cells may require MDM2 to proliferate and survive even when p53 is absent or mutated.…”

“…Wienken et al show that MDM2, independently of p53, is required for efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts (MEFs), as well as to suppress osteoblast differentiation of multipotent mesenchymal stem cells and promote proliferation of cancer cells (Wienken et al, 2016). The authors find that Tpr53 À/À ;Mdm2 À/À MEFs reprogram much more efficiently than Tpr53 À/À MEFs.…”

“…Previous studies had uncovered MDM2 interactions with histone methyl transferases SUV39H1 and EHMT1 to target MDM2 RING-dependent histone H2B ubiquitination to chromatin, with or without p53, and repress transcription (Minsky and Oren, 2004). Wienken et al found that MDM2 physically associates with the PRC2 complex and enhances both H3K27me3 and H2AK119ub1 in a RING-domain-dependent manner to suppress PRC2-target, development-associated genes and induce pluripotency (Wienken et al, 2016).…”

“…Evidence mounts, via two studies published in Molecular Cell (Riscal et al, 2016;Wienken et al, 2016), that chromatin-bound MDM2 impacts pluripotency and metabolism to promote survival and proliferation of cancer cells, independently of p53 degradation.…”

“…However, accumulating evidence suggests that MDM2 embraces activities beyond its RING domain E3-ligase, both dependently and independently of p53, by localizing to promoter DNA to effect or block post-translational modification of associated transcription factors or histones (Biderman et al, 2012). To gain more mechanistic insights into the regulatory impact of MDM2 interactions with chromatin, the authors of two studies published in Molecular Cell utilized high-throughput sequencing approaches to reveal a global view of transcription regulation by chromatinbound MDM2, whether p53 independent or dependent (Riscal et al, 2016;Wienken et al, 2016). Together, these studies show that MDM2 can function as either a transcription co-activator (Riscal et al, 2016) or a transcription co-repressor (Wienken et al, 2016) to regulate gene expression in a contextspecific manner, plus or minus p53, and promote somatic cell reprograming, ''stemness,'' metabolic rewiring, and cancer cell proliferation.…”