Dissertation/Thesis Abstract

Chromatin Dynamics in Melanoma Progression and Senescence: A Novel Role for the Histone Variant macroH2A
by Kapoor, Avnish, Ph.D., Mount Sinai School of Medicine, 2011, 212; 3474829
Abstract (Summary)

Cancer is a disease consisting of both genetic and epigenetic changes. Although increasing evidence demonstrates that tumor initiation (for example, by evasion of cellular senescence) and progression (for example, proliferation and metastasis) entails chromatin-mediated changes such as DNA methylation and histone modifications, the role of histone variants in these processes remains unclear. Histone variants replace conventional histones within the nucleosome and confer unique biological functions to chromatin.

In this dissertation, I report the novel finding that the histone variant macroH2A (mH2A) suppresses tumor 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. I demonstrate that the tumor-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. These findings demonstrate that mH2A is a critical component of chromatin that suppresses the development of malignant melanoma, a highly intractable cutaneous neoplasm.

In this dissertation, I also report the first high-throughput study focused on the global chromatin changes (histone modifications and histone variants) that occur during induction of cellular senescence, a vital mechanism that constrains the malignant progression of tumors. This work demonstrates numerous chromatin changes (e.g. increase of mH2A and loss of H2A.Z), some of which have not yet been reported (e.g. H3 tail clipping and increase of H4K20me3). I examined if these changes are functionally required for oncogene-induced growth arrest. Here, I again focused my efforts on mH2A. While upregulated in cellular senescence, the role of this variant has yet to be determined. However, my preliminary data suggests mH2A plays an active role in this process. The data presented here has implications for our understanding of this important tumorigenesis regulatory mechanism.

Indexing (document details)
Advisor: Bernstein, Emily
Commitee: Aaronson, Stuart A., Aguirre-Ghiso, Julio A., Allis, C. David, O'Connell, Matthew J., Warburton, Peter
School: Mount Sinai School of Medicine
Department: Genetics and Genomic Sciences
School Location: United States -- New York
Source: DAI-B 73/01, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Cellular biology
Keywords: Cancer epigenetics, Chromatin, Histone variants, Melanoma, Senescence, Tumor suppressor
Publication Number: 3474829
ISBN: 9781124917719