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 genetic loss of function of tumor suppressor genes and over activity 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 to develop 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 that is involved in epigenetic gene silencing, suppression of recombination and maintenance of chromatin functions. Increasing Sir2 or SIRT1 gene dosage or enzymatic activity promotes longevity in multiple lower organisms and 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 found in human and mouse cancers, however precise roles of SIRT1 in tumorigenesis are not well defined. Other members of SIRT1 gene family termed sirtuins may also regulate cell metabolism and aging, but little is known for their functions in cancer.Current research themes in the lab are: (1) investigating roles of SIRT1 in BCR-ABL transformation of primitive hematopoietic progenitor cells and chemoresistance of chronic myelogenous leukemia to tyrosine kinase inhibitors. (2) studying functions of sirtuins and NAD metabolism in prostate epithelial cells and carcinogenesis.Our goals are to discern how sirtuins are involved in regulating cellular longevity and tumorigenesis, and develop strategies for healthy aging and reducing cancer risk.