WenYong Chen, Ph.D.
- Associate Professor, Department of Cancer Biology, Beckman Research Institute
WenYong Chen, Ph.D.
- Cancer Biology
- 2012-present Associate Professor, Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California
- 2005-present Full member, Comprehensive Cancer Center of City of Hope, Duarte, California
- 2005-present Faculty, City of Hope Graduate School, Duarte, California
- 2005 - 2011 Assistant Professor, Division of Biology, Beckman Research Institute, City of Hope, Duarte, California
- 2000 - 2005 Postdoctoral Fellow, Cancer Biology Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
- 1993 - 1999 Graduate Program of Cellular and Molecular Biology, and Graduate Research Assistant in Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham.
- Cancer Biology
- 1999 Ph.D. Molecular Biology, University of Alabama at Birmingham
- 1985 B.S. Chemistry Zhejiang University, China
- 2005 Post-doc Fellowship, Cancer Biology, Johns Hopkins University
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.
- Wang Z., Chen, C.C., and Chen, W.Y. (2015) CD150- side population defines leukemia stem cells in a mouse model of chronic myelogenous leukemia in BABL/c mice and is depleted by genetic loss of SIRT1. Stem Cells. (In press)
- Chen, WY. (2014) SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol (Hyperlink)
- Li L, Osdal T, Ho Y, Chun S, McDonald T, Agarwal P, Lin A, Chu S, Qi J, Li L, Hsieh YT, Dos Santos C, Yuan H, Ha TQ, Popa M, Hovland R, Bruserud O, Gjertsen BT, Kuo YH, Chen WY, Lain S, McCormack E, Bhatia R. (2014) SIRT1 activation by a c-MYC Oncogenic Network Promotes the Maintenance and Drug Resistance of Human FLT3-ITD Acute Myeloid Leukemia Stem Cells. Cell Stem Cell. 15: 431-46. PMID: 25280219
- Wang, Z., Liu, Z., Wu X., Chu, S., Wang, J.H., Yuan, H., Roth, M., Yuan, Y.C., Bhatia, R. and Chen, W.Y. (2014) ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance. PloS Genet 10: e1004414. PMID: 24967705
- Roth, M. and Chen W.Y. (2014) Sorting out functions of sirtuins in cancer. Oncogene. 33(13):1609-20. PMID: 23604120
- Roth,M., Wang, Z. and Chen W.Y. (2013) Sirtuins in hematological aging and malignancy. Critical Reviews in Oncogenesis. 18(6):485-501.
- Yuan, H. Su, L. and Chen, W.Y. (2013) The emerging and diverse roles of sirtuins in cancer: A clinical perspective. Oncotarget & Therapy 6:1399-1416.
- Wang, Z. and Chen, W.Y. (2013) Emerging roles of SIRT1 in cancer drug resistance. Genes & Cancer. 4: 82-90.
- Chen, W.Y. and Bhatia, R. (2013) Roles of SIRT1 in leukemogenesis. Curr Opin Hematol 20: 308-313.
- Wang, Z., Yuan, H., Roth M., Stark, J., Bhatia, R. and Chen, W.Y. (2013) SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene 32: 589-598. PMID: 22410779; PMCID: PMC3376246.
- Chen, W.Y. (2012) Accelerating cancer evolution: a dark side of SIRT1 in genome maintenance. Oncotarget 3: 363-364.
- Chakraborty, S., Stark, J.M., Sun,C.L., Modi, H., Chen, W.Y., O’Connor T., Forman, S.J., Bhatia, S., and Bhatia R. (2012) Chronic Myelogenous Leukemia Stem and Progenitor Cells Demonstrate Chromosomal Instability Related to Repeated Breakage-Fusion-Bridge Cycles Mediated by Non-Homologous End Joining. Blood 119: 6187-6197. PMCID: PMC3383199
- Nam S., Scuto A., Yang F., Chen W.Y., Park S., Yoo H.S., Konig H., Bhatia R., Cheng X., Merz K.H., Eisenbrand G., and Jove R. (2012) Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of STAT5 signaling. Molecular Oncology 6: 276-283.
- Yuan, H., Wang, Z ., Zhang, H., Bhatia, R. and Chen, W.Y. (2012) Overcoming CML acquired resistance by specific inhibition of Aurora A kinase in the KCL-22 cell model. Carcinogenesis 33: 285-293. PMID: 22116466; PMCID: PMC3271265
- Li, L., Wang, L., Li, L., McDonald, T., Ho, Y., Holyoake T., Chen, W.Y.# and Bhatia, R. # (2012) Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with Imatinib. Cancer Cell 21: 266-281. PMCID: PMC3285436. #Co-corresponding authors.
- Yuan, H., Wang, Z., Li, L., Zhang, H., Modi, H., Horne, D., Stark, J., Bhatia, R. # and Chen, W.Y. # (2012) Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 119: 1904-1914. PMID: 22207735; PMCID: PMC3293644 #Co-corresponding authors.
- Wang, B., Hasan, K.M., Alvarado, E., Yuan, H., Wu, H. and Chen, W.Y. (2011) NAMPT over-expression in prostate cancer and its contribution to tumor cell survival and stress response. Oncogene 30: 907-921. PMID: 20956937
- Chen, W.Y., Yuan, H. and Wang, Z. (2011) De novo acquisition of BCR-ABL mutations for CML acquired resistance. In Myeloid Leukemia: Basic Mechanisms of Leukemogenesis. Steffen Koschmieder and Utz Krug (eds). pp 69-84. (Hyperlink)
- Yuan, H., Wang, Z., Gao, C., Chen, W., Huang, Q., Yee, J.K., Bhatia, R., and Chen, W.Y. (2010) BCR-ABL gene expression is required for its mutations in a novel KCL-22 cell culture model for acquired resistance of chronic myelogenous leukemia. J Biol Chem 285:5085-5096. PMCID: PMC2836111
- Chen W.Y., Wang, D.H., Chiu, R.W., Lou, J.Y., Gu, W, and Baylin, S.B. (2005) Tumor suppressor HIC1 directly regulates SIRT1 deacetylase to modulate p53-dependent apoptotic DNA damage responses. Cell, 123:437-448. PMID: 16269335
- Chen, W.Y., Cooper, T.K., Zahnow, C.A., Overholtzer, M, Zhao, Z, Ladanyi, M., Karp, .E., Gokgoz, N., Wunder, J.S., Andrulis, I.L., Levine, A.J., Mankowski, J.L., & Baylin, S.B. (2004) Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell, 6:387-398. PMID: 15488761.
- Chen W.Y., Zeng X., Carter M.G., Morrell C.N., Chiu Yen R.W., Esteller M., Watkins D.N., Herman J.G., Mankowski J.L. & Baylin S.B. (2003) Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet, 33, 197-202. PMID: 12539045.
- Chen W.Y., Wu X., Levasseur D.N., Liu H., Lai L., Kappes J.C. & Townes T.M. (2000) Lentiviral vector transduction of hematopoietic stem cells that mediate long-term reconstitution of lethally irradiated mice. Stem Cells, 18, 352-359.
- Chen W.Y. & Townes T.M. (2000) Molecular mechanism for silencing virally transduced genes involves histone deacetylation and chromatin condensation. Proc Natl Acad Sci U S A, 97, 377-382. PMID: 10618426; PMCID: PMC26671.
- Chen W.Y., Bailey E.C., McCune S.L., Dong J.Y. & Townes T.M. (1997) Reactivation of silenced, virally transduced genes by inhibitors of histone deacetylase. Proc Natl Acad Sci U S A, 94, 5798-5803. PMID: 9159154; PMCID: PMC20860