Epigenetic modifications play important roles in many normal biological processes, such as development, stem cell differentiation and aging, as well as in disease settings such as cancer. Cancer evolves with 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 aging, tumorigenesis and cancer drug resistance.
Roles of SIRT1 in hematopoietic stem cells and leukemic stem cells
Sirtuin 1 (SIRT1) is a mammalian stress-response gene encoding an NAD-dependent protein deacetylase. SIRT1 deacetylates histones and non-histone proteins, and plays diverse roles in regulating metabolism, aging and cancer. SIRT1 has been considered a gene to promote longevity; however, over-expression of SIRT1 occurs in various types of human and murine cancers. To define roles of SIRT1 in cancer, we have shown that SIRT1 is activated by oncogenic transformation of hematopoietic stem cells, and promotes leukemogenesis and drug resistance of leukemic stem cells to chemotherapeutic agents. SIRT1 inhibition by small molecules or genetic deletion sensitizes leukemia cells to chemotherapy and depletes leukemia stem cells. Our studies suggest that SIRT1 is a promising therapeutic target for treatment of leukemia and perhaps other malignancies. We will further decipher roles of SIRT1 in hematopoietic stem cells during aging and leukemogenesis and develop novel SIRT1 inhibitors for cancer treatment.
Mechanisms of mutation acquisition for cancer drug resistance
Acquisition of resistant genetic mutations underlies a major therapeutic hurdle for targeted cancer therapies. It is believed that rare mutant cells in the bulk of cancer cells can be selected to mediate drug resistance. However, the origin of these rare mutant cells is an issue of debate. It is known in bacteria that mutations can be induced de novo in response to environmental stress, termed adaptive mutagenesis. We have developed by serendipity a mammalian model system of mutation acquisition using chronic myeloid leukemia (CML) cells, and shown that resistant BCR-ABL genetic mutations can be acquired de novo in CML cells in response to treatment with tyrosine kinase inhibitors. The de novo mutation acquisition in human cancer cells involves error-prone DNA damage repair and regulation of such repair by SIRT1 and other epigenetic factors. Further elucidating mechanisms of mutation acquisition may help devise novel therapeutic strategies for cancer and prevent disease relapse.
NAD metabolism and sirtuins in solid tumors
Mammalian sirtuin family genes contain seven members (SIRT1-7) with different cellular localization and biological roles. All sirtuins depend on the cofactor NAD for enzymatic activity. We have shown that NAD salvage biosynthesis enzyme NAMPT is concomitantly over-expressed with SIRT1 and mediates cell survival and stress resistance of prostate cancer. Other members of sirtuins may also play diverse roles in solid tumors. Much is needed to examine the functions of sirtuins and NAD metabolism in epithelial cells and carcinogenesis as well as cancer therapeutic response.