Dual Roles of RNF2 in Melanoma Progression #MMPMID26450788
Rai K; Akdemir KC; Kwong LN; Fiziev P; Wu CJ; Keung EZ; Sharma S; Samant NS; Williams M; Axelrad JB; Shah A; Yang D; Grimm EA; Barton MC; Milton DR; Heffernan TP; Horner JW; Ekmekcioglu S; Lazar A; Ernst J; Chin L
Cancer Discov 2015[Dec]; 5 (12): 1314-27 PMID26450788show ga
Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is oncogenic and pro-metastatic. Mechanistically, RNF2-mediated invasive behavior is dependent on its ability to mono-ubiquitinate H2AK119 at the promoter of LTBP2, resulting in silencing of this negative regulator of TGF? signaling. In contrast, RNF2's oncogenic activity does not require its catalytic activity nor does it derive from its canonical gene repression function. Instead, RNF2 drives proliferation through direct transcriptional up-regulation of the cell cycle regulator CCND2. We further show that MEK1 mediated phosphorylation of RNF2 promotes recruitment of activating histone modifiers UTX and p300 to a subset of poised promoters, which activates gene expression. In summary, RNF2 regulates distinct biological processes in the genesis and progression of melanoma via different molecular mechanisms.
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Cancer+Discov 2015 ; 5 (12): 1314-27
