Dual Roles of RNF2 in Melanoma Progression

Abstract

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 TGFβ 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.

RNF2 E3 or Not to E3: Dual Roles of RNF2 Overexpression in Melanoma

“…The LTBP2 promoter was directly bound by RNF2 in overexpressing cells with a concomitant increase in H2AK119ub. In agreement with these observations, knockdown of LTBP2 resulted in the up-regulation of TGF-β targets (ID1-3) (5). Consistent with a role for increased TGFβ signaling, RNF2-mediated invasion was suppressed by the TGFβ signaling inhibitor LY2157299 (Figure 1).…”

“…The biological consequences of this overexpression remain elusive; however, RNF2 was recently identified in a signature for invasive melanomas (4). Therefore, Rai and colleagues set out to ascertain a role for RNF2 in melanoma tumorigenesis and metastasis (5). Higher RNF2 expression levels correlate with progression and metastasis in melanoma.…”

“…RNF2 overexpression also promoted soft agar growth and tumorigenic potential of melanoma cell lines. However, a surprising result came when it was revealed that only the pro-invasion properties of RNF2 required the catalytic activity of the E3 ligase RING domain, while the pro-oncogenic promotion of proliferation and anchorage independent growth was catalytically-independent (Figure 1) (5). …”

“…RNF2 bound and regulated transcripts were split between repressed transcripts (47%), which represents the classic repressive function of RNF2, and upregulated transcripts (53%), representing a new possible transcriptional activation function (5). …”

“…It remains unclear if overexpression of Ring1A also promotes invasion or tumorigenesis (Figure 1). Rai and colleagues clearly demonstrate that in melanoma RNF2 is necessary and sufficient for suppression of LTBP2 and modulating invasion and metastasis (5); however, it is possible that Ring1A could potentiate similar effects in other tissue or tumor types. It will be important to determine the unique and overlapping targets for RNF2 and Ring1A and what specifies these differences.…”