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Chromatin Dynamics in Melanoma: A Role for MacroH2A

By M. Goldberg, L. Cumberland, K. Ratnakumar, M. Segura, P. Emanuel, S. Menendez, C. Vardabasso, G. LeRoy, C. Vidal, D. Polsky, I. Osman, B. Garcia, E. Hernando, E. Bernstein and A. Kapoor

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. Using well characterized, paired series of murine and human melanoma cells lines, we probed the epigenetic profile of melanoma. Analysis of histones from both series using multiplexed quantitative mass spectrometry revealed changes in several histone posttranslational modifications and histone variants. The 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

Topics: Scientific Session Abstracts
Publisher: Association of Biomolecular Resource Facilities
OAI identifier: oai:pubmedcentral.nih.gov:3186562
Provided by: PubMed Central
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