Epigenetics, Cancer and Aging
DNA methylation and histone modification affect mammalian gene regulations and functions. These epigenetic modifications play important roles in many normal biological processes, such as development, stem cell differentiation and aging, as well as in several mental retardation diseases and cancer. Cancer evolves with the genetic loss of function of tumor suppressor genes and overactivity of oncogenes. Meanwhile, cancer progression also involves profound epigenetic deregulation of tumor suppressor genes, and chromatin alterations that affect genomic stability and gene expression. We are interested in understanding the biology of cancer with a focus on epigenetic regulation of tumor suppressor genes and oncogenes in development, aging and tumorigenesis, and developing mouse models for studying cancer epigenetics and testing strategies for cancer prevention and therapy.
Using mouse genetics, we demonstrate the important roles of an epigenetically regulated gene, hypermethylated in cancer 1(HIC1), in tumor suppression. We show that a key role for loss of HIC1 function in tumorigenesis is to activate the mammalian stress-response gene SIRT1 (an NAD-dependent protein deacetylase) and thereby deacetylate and inactivate p53. SIRT1 is a homologue of yeast Sir2 protein, a histone deacetylase that is involved in epigenetic gene silencing, suppression of recombination and maintenance of chromatin functions. SIRT1 protects mammalian cells from apoptosis under stress and DNA damage. Since aging increases promoter hypermethylation and epigenetic silencing of HIC1, these studies suggest that the resultant upregulation of SIRT1 may be a double-edged sword that both promotes survival of aging cells and increases cancer risk in mammals.
SIRT1 over-expression is prevalent in human and mouse cancers; however, the precise roles of SIRT1 in tumorigenesis are not well defined. Other members of the SIRT1 gene family termed sirtuins may also regulate cell metabolism and aging, but their functions in cancer are not well understood. The current research themes in the lab include investigating the roles of SIRT1 in BCR-ABL transformation of primitive hematopoietic progenitor cells and chemoresistance of chronic myelogenous leukemia to tyrosine kinase inhibitors, and studying the functions of sirtuins and NAD metabolism in epithelial cells and carcinogenesis. Our goals are to discern how sirtuins are involved in regulating cellular longevity and tumorigenesis and to develop strategies for healthy aging and reduced cancer risk.