title: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. lchin@mdanderson.org krai@mdanderson.org.
authors.forename: Kunal
authors.initials: K
authors.lastname: Rai
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kadir C
authors.initials: KC
authors.lastname: Akdemir
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.affiliation: Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, California. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
authors.forename: Petko
authors.initials: P
authors.lastname: Fiziev
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chang-Jiun
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Emily Z
authors.initials: EZ
authors.lastname: Keung
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sneha
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Neha S
authors.initials: NS
authors.lastname: Samant
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maura
authors.initials: M
authors.lastname: Williams
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Axelrad
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Amiksha
authors.initials: A
authors.lastname: Shah
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grimm
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Barton
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Denai R
authors.initials: DR
authors.lastname: Milton
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: James W
authors.initials: JW
authors.lastname: Horner
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, California. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California. Departments of Biological Chemistry and Computer Science, University of California, Los Angeles, Los Angeles, California. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Ernst
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas. Institute for Health Transformation, The University of Texas System, Houston, Texas. lchin@mdanderson.org krai@mdanderson.org.
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
mesh_terms: D000818:Animals; D002384:Catalysis; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism; D009857:Oncogenes; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; C509035:LTBP2 protein, human; D053779:Latent TGF-beta Binding Proteins; D009687:Nuclear Proteins; D016212:Transforming Growth Factor beta; D056466:Histone Demethylases; C523998:KDM6A protein, human; D050881:E1A-Associated p300 Protein; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human