title: The histone variant macroH2A suppresses melanoma progression through regulation of CDK8.
abstract: Cancer is a disease consisting of both genetic and epigenetic changes. Although increasing evidence demonstrates that tumour progression entails chromatin-mediated changes such as DNA methylation, the role of histone variants in cancer initiation and progression currently remains unclear. Histone variants replace conventional histones within the nucleosome and confer unique biological functions to chromatin. Here we report that the histone variant macroH2A (mH2A) suppresses tumour progression of malignant melanoma. Loss of mH2A isoforms, histone variants generally associated with condensed chromatin and fine-tuning of developmental gene expression programs, is positively correlated with increasing malignant phenotype of melanoma cells in culture and human tissue samples. Knockdown of mH2A isoforms in melanoma cells of low malignancy results in significantly increased proliferation and migration in vitro and growth and metastasis in vivo. Restored expression of mH2A isoforms rescues these malignant phenotypes in vitro and in vivo. We demonstrate that the tumour-promoting function of mH2A loss is mediated, at least in part, through direct transcriptional upregulation of CDK8. Suppression of CDK8, a colorectal cancer oncogene, inhibits proliferation of melanoma cells, and knockdown of CDK8 in cells depleted of mH2A suppresses the proliferative advantage induced by mH2A loss. Moreover, a significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples. Taken together, our results demonstrate that mH2A is a critical component of chromatin that suppresses the development of malignant melanoma, a highly intractable cutaneous neoplasm.
authors.affiliation: Department of Oncological Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Avnish
authors.initials: A
authors.lastname: Kapoor
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Lara K
authors.initials: LK
authors.lastname: Cumberland
authors.forename: Kajan
authors.initials: K
authors.lastname: Ratnakumar
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Segura
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Emanuel
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Chiara
authors.initials: C
authors.lastname: Vardabasso
authors.forename: Gary
authors.initials: G
authors.lastname: Leroy
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Vidal
authors.forename: David
authors.initials: D
authors.lastname: Polsky
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006657:Histones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000473:pathology* / Q000503:physiopathology; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D015854:Up-Regulation
chemical_list: D006657:Histones; C120756:macroH2A histone; D056850:Cyclin-Dependent Kinase 8