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 chromatin1,2,3. 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 programs1,4,5,6, 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 oncogene7,8, 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gene Expression Omnibus
Microarray data are deposited in National Center for Biotechnical Information Gene ExpressionOmnibus under accession number GSE19181.
We thank G. Hannon, S. Hake and M. Wirtz for reading this manuscript; J. Doucette for statistical support; the laboratories of S. Aaronson, J. Aguirre-Ghiso, D. Burstein and M. O’Connell for discussions and advice; M. Lebwohl, S. Mercer, J. Emer and G. Singer for dermatology and pathology support. We also thank N. Mall, L. Murray, S. Malu and S. Mungamuri for technical assistance; J. Pehrson, M. Narita, A. Aplin, H. Wei, A. Ting, S. Young Kim, M. Herlyn and J. Espinosa for reagents; T. Chu (Mount Sinai School of Medicine Microarray SRF) for data analysis; Q. Yu, the New York University Interdisciplinary Melanoma Cooperative Group and Mount Sinai Biorepository Cooperative for melanoma specimens. This work was supported by an American Skin Association Medical Student Grant to M.S.G., American Society for Mass Spectrometry Award, New Jersey Commission on Cancer Research Seed Grant, and National Science Foundation CBET-0941143 to B.A.G., National Institutes of Health CA109388 and the Sergei S. Zlinkoff Fund for Medical Education to D.P., New York University Cancer Institute Cancer Center Support Grant (5P30CA016087-27) and Marc Jacobs Campaign to I.O., NYSTEM IDEA C024291 and Harry L. Lloyd Charitable Trust to E.H., and an American Skin Association Research Scholar Award, Ellison Medical Foundation New Scholar Award, Tisch Cancer Institute Developmental Funds and NCI R21CA150117 to E.B.
About this article