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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 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.

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Figure 1: mH2A loss correlates with increasing melanoma malignancy.
Figure 2: mH2A depletion and ectopic expression alter malignant properties of melanoma cells in vitro and in vivo.
Figure 3: Microarray and ChIP analyses identify CDK8 as a direct mH2A-regulated gene in melanoma.
Figure 4: CDK8 is a major effector of mH2A loss.

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Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in National Center for Biotechnical Information Gene ExpressionOmnibus under accession number GSE19181.

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Acknowledgements

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.

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Authors

Contributions

A.K., M.S.G., K.R. and E.B. conceived ideas and experimental design. A.K. generated shRNA and overexpression cell lines and performed all in vitro and in vivo studies, DNA methylation analysis, microarray studies, qPCR and ChIP. M.S.G. performed immunoblots, IHC and statistical analysis. L.K.C. performed IHC, immunoblots and in vivo studies, and K.R. performed MNase studies. C.V. performed ChIP, and P.O.E. and C.I.V. scored and evaluated all human and mouse tissues. S.M., M.F.S. and E.H. designed and performed mouse studies, G.L. and B.A.G. performed and analysed quantitative mass spectrometry studies, and D.P. and I.O. contributed critical reagents. E.B. wrote the manuscript with contributions from all other authors.

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Correspondence to Emily Bernstein.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-23 with legends and Supplementary Tables 1-4 and additional references. (PDF 5693 kb)

Supplementary Table 5

This excel file is appended with probe changes and intersections in microarray experiment #1. (XLS 228 kb)

Supplementary Table 6

This excel file is appended with probe changes and intersections in microarray experiment #2. (XLS 121 kb)

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Kapoor, A., Goldberg, M., Cumberland, L. et al. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature 468, 1105–1109 (2010). https://doi.org/10.1038/nature09590

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