Research Description
The cancerous cellular state is associated with multiple chromatin alterations, but elucidating the precise order of such alterations during tumorigenesis and their contributions to the clinical progression of the disease remain significant challenges in cancer biology. Our laboratory seeks to understand how histones and their post-translational modifications contribute to cancer initiation and progression. Our approach is twofold: 1) we identify alterations of the epigenome that are related to the cancer’s clinical behavior directly from primary cancer tissues and pursue the biological bases of these alterations in the laboratory through reductionist approaches using model systems; 2) we exploit the ability of DNA tumor viruses to transform normal human cells to cancerous ones to determine the early epigenetic alterations that may drive cancer initiation. Our two-pronged strategy has provided an important advantage: recognition of novel phenomena that are not readily discernable from the current paradigms for the function of histone modifications. Pursuit of these phenomena has led to unanticipated biological discoveries about the function of chromatin and its alterations in cancer. These findings include the first predictive association of epigenetic alterations with clinical outcome of cancer patients, discovery of an unusual function of histones in regulation of intracellular pH, identification of a unique histone acetylation site as a critical target for oncogenic transformation by viral oncogenes, and uncovering an evolutionary function of the core histones for genome compaction that may also explain certain histones are mutated in cancer.