Cancer has historically been viewed as a result of mutations that lead to the activation of oncogenes and/or the inactivation of tumor suppressor genes. However, since the initial report in 1983 describing an altered DNA methylation pattern in cancer, it has become clear that epigenetic alterations, changes in patterns of DNA methylation and histone modifications, importantly contribute to human carcinogenesis. Epigenetic aberrations result in heritable changes in chromatin structure and gene expression with functional consequences akin to those induced by genetic mutations. Hence, cancer is as much an epigenetic disease as it is a genetic disease. In stark contrast to the irreversible nature of genetic mutations, epigenetic aberrations are potentially reversible, thus allowing for therapeutic intervention. The overall goal of this career development proposal is to assist in establishing the independent academic career of Dr. McLaughlin-Drubin in the study of cancer epigenetics and specifically of HPV subversion of host epigenetic programs. The training environments are in the laboratories of the co-mentors, Dr. Karl M|nger at Brigham and Women's Hospital/Harvard Medical School and Dr. Yang Shi at Harvard Medical School.
The specific aims of the proposed research project focus on elucidating the mechanism of HPV E7 epigenetic reprogramming. The candidate's preliminary data has shown that histone H3 lysine27 trimethylation (H3K27me3), an epigenetic modification that silences chromatin, as well as E2F6-PcG repressor complexes that normally bind to silenced chromatin, are decreased in HPV16 E7 expressing cells. In addition, the candidate discovered that HPV16 E7 induces the enzymes that remove this repressive histone modification, the histone demethylases UTX and JMJD3. Moreover, a subset of UTX- and JMJD3-responsive HOX genes are expressed at markedly higher levels in HPV16 E7 expressing cells, and E7 mediated JMJD3 over- expression is critical for p16INK4A expression.
The first aim of the proposed research is to determine the mechanism of HPV E7 induced epigenetic reprogramming.
The second aim focuses on biological endpoints of this epigenetic reprogramming, including the potential role in carcinogenesis.
The expression of the human papillomavirus (HPV) E6 and E7 oncoproteins is necessary for the induction and maintenance of the transformed state, which makes cervical cancer a unique model to study human cancer development. Therefore, cervical cancer provides a well-defined system of cancer development to study the regulation of polycomb group proteins and histone demethylases and the functional consequences of their deregulation in cancer. A detailed mechanistic understanding of epigenetic changes that occur during cervical cancer development, specifically those directly caused by HPV oncoproteins, will provide critical insights into the development of human solid tumors.
