Dual Roles of RNF2 in Melanoma Progression
| Autor: | Dong Yang, Lynda Chin, Sneha Sharma, Jason Ernst, Timothy P. Heffernan, Alexander J. Lazar, Michelle Craig Barton, James W. Horner, Chang-Jiun Wu, Denái R. Milton, Jacob B. Axelrad, Petko Fiziev, Suhendan Ekmekcioglu, Maura Williams, Emily Z. Keung, Lawrence N. Kwong, Elizabeth A. Grimm, Amiksha Shah, Kadir C. Akdemir, Kunal Rai, Neha S. Samant |
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| Rok vydání: | 2015 |
| Předmět: |
MAP Kinase Signaling System
1.1 Normal biological development and functioning Oncology and Carcinogenesis Regulator Gene Expression Context (language use) Cell Transformation Catalysis Promoter Regions Mice Cyclin D2 Genetic Transforming Growth Factor beta Underpinning research Genetics Gene silencing Animals Humans 2.1 Biological and endogenous factors Epigenetics Neoplasm Metastasis Phosphorylation Aetiology Melanoma Cancer Regulation of gene expression Histone Demethylases Polycomb Repressive Complex 1 Neoplastic biology Nuclear Proteins Oncogenes Cell cycle Prognosis Histone Oncology Gene Expression Regulation Latent TGF-beta Binding Proteins biology.protein Cancer research Disease Progression E1A-Associated p300 Protein Biotechnology |
| Zdroj: | Cancer discovery, vol 5, iss 12 |
| Popis: | 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 prometastatic. Mechanistically, RNF2-mediated invasive behavior is dependent on its ability to monoubiquitinate 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 upregulation 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 biologic processes in the genesis and progression of melanoma via different molecular mechanisms. Significance: The role of epigenetic regulators in cancer progression is being increasingly appreciated. We show novel roles for RNF2 in melanoma tumorigenesis and metastasis, albeit via different mechanisms. Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes. Cancer Discov; 5(12); 1314–27. ©2015 AACR. See related commentary by Black and Whetstine, p. 1241. This article is highlighted in the In This Issue feature, p. 1225 |
| Databáze: | OpenAIRE |
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