Dual Roles of RNF2 in Melanoma Progression.
Dual Roles of RNF2 in Melanoma Progression.
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DOI：
10.1158/2159-8290.cd-15-0493
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发表时间：
2015-12
期刊：
影响因子：
28.2
通讯作者：
Chin L
中科院分区：
文献类型：
--
作者：
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 AJ;Ernst J;Chin L
表观遗传调节因子已成为控制癌症生物学的关键因素。在这里，在黑色素瘤的背景下，我们表明，RNF2是预后，在人类黑色素细胞肿瘤中表现出进展相关的表达。通过在小鼠和人类系统中进行的一系列互补的功能获得和功能丧失研究，我们确定了RNF2是致癌的和促转移的。从机制上讲，RNF2介导的侵袭行为依赖于其在LTBP 2启动子处单泛素化H2AK119的能力，导致TGFβ信号传导的负调节因子沉默。相反，RNF2的致癌活性不需要其催化活性，也不源自其典型的基因抑制功能。相反，RNF2通过细胞周期调节因子CCND2的直接转录上调来驱动增殖。我们进一步表明，MEK1介导的RNF2磷酸化促进激活组蛋白修饰剂UTX和p300的募集到一个子集的准备启动子，激活基因表达。总之，RNF2通过不同的分子机制调节黑色素瘤发生和进展中的不同生物学过程。
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.