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2017 ; 9
(1
): 74-80
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Mdm2 as a chromatin modifier
#MMPMID27927750
Wienken M
; Moll UM
; Dobbelstein M
J Mol Cell Biol
2017[Feb]; 9
(1
): 74-80
PMID27927750
show ga
Mdm2 is the key negative regulator of the tumour suppressor p53, making it an
attractive target for anti-cancer drug design. We recently identified a new role
of Mdm2 in gene repression through its direct interaction with several proteins
of the polycomb group (PcG) family. PcG proteins form polycomb repressive
complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27)
trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119)
monoubiquitination. Both PRCs mostly support a compact and transcriptionally
silent chromatin structure. We found that Mdm2 regulates a gene expression
profile similar to that of PRC2 independent of p53. Moreover, Mdm2 promotes the
stemness of murine induced pluripotent stem cells and human mesenchymal stem
cells, and supports the survival of tumour cells. Mdm2 is recruited to target
gene promoters by the PRC2 member and histone methyltransferase EZH2, and
enhances PRC-dependent repressive chromatin modifications, specifically H3K27me3
and H2AK119ub1. Mdm2 also cooperates in gene repression with the PRC1 protein
RING1B, a H2AK119 ubiquitin ligase. Here we discuss the possible implications of
these p53-independent functions of Mdm2 in chromatin dynamics and in the stem
cell phenotype. We propose that the p53-independent functions of Mdm2 should be
taken into account for cancer drug design. So far, the majority of clinically
tested Mdm2 inhibitors target its binding to p53 but do not affect the new
functions of Mdm2 described here. However, when targeting the E3 ligase activity
of Mdm2, a broader spectrum of its oncogenic activities might become druggable.
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