Dr. Hsing-Jien Kung

 

Hsing-Jien Kung, Ph.D.

Distinguished Investigator
Institute of Molecular and Genomic Medicine
hkung@nhri.org.tw

EDUCATION

Ph.D., Chemistry, California Institute of Technology  (1975)
B.S. Chemistry, National Taiwan University  (1969)

PROFESSIONAL EXPREIENCE

1970-1976 Graduate Research Assistant, California Institute of Technology (at Norman Davidson’s lab)

1977-1978 Research Associate, University of California, San Francisco (at J.M. Bishop and H.E. Varmus’s lab)

1978-1982 Assistant Professor, Department of Biochemistry, Michigan State University

1982-June 1984 Associate Professor, Department of Biochemistry, Michigan State University

June 1984-July 1988 Associate Professor, Dept. of Molecular Biology & Microbiology, CWRU School of Medicine

July 1988-1998 Professor, Dept. of Molecular Biology & Microbiology, CWRU School of Medicine

1989-1998 Professor, Department of Medicine, Case Western Reserve University School of Medicine

1990-1998 Associate Director of Basic Science, CWRU Cancer Center

1998- 2008 Professor, Dept. Biochemistry and Molecular Medicine, UC Davis, School of Medicine

1998- 2008 Deputy Director and Director of Basic Research, UC Davis Cancer Center

2008- Present Distinguished Professor, Dept. Biochemistry and Molecular Medicine, UC Davis, School of Medicine

2012-2015 President, National Health Research Institutes, Taiwan.

2012- Present Distinguished Professor, Institute Molecular and Genomic Medicine, National Health Research Institutes, Taiwan

RESEARCH INTERESTS

Oncogenes and Oncogenesis

My earlier work using retroviral mutational analysis revealed for the first time how EGFR mutation in the kinase and C-terminal domain affect its oncogenecity. Many of the EGFR mutations discovered a decade later confirmed our original hypothesis. My lab was also the first to demonstrate the oncogenecity of v-Src DNA in vivo using direct injection model. Subsequently, my lab cloned several tyrosine kinase oncogenes including Etk/BMX and Nyk/merTK, both shown to be implicated in prostate cancer. We also showed how Src/Etk signaling can aberrantly activate androgen receptor, conferring hormone-resistance. In recent years, we began our work of developing tyrosine kinase inhibitors and studying Src inhibitor in prostate cancer. We have now developed several Etk/Btk inhibitors and shown their efficacies in vitro and in preclinical studies. With respect to Src inhibitor, we found it inhibits the activation of beta-catenin, STAT-3 and c-myc, as well as the induction of tumor suppressive microRNA. Most importantly, we found Src or Etk inhibitors induce autophagy which causes apoptosis-resistance. The addition of autophagy inhibitor overcomes such a resistance. We have extended the analysis to nutritional starvation as a potential therapy for cancers, and found inhibition of autophagy also render the strategy more efficacious. In the course of these studies, we found arginine deprivation is an effective way to treat cancer cells which are addicted to external arginine. Finally, we have characterized the androgen receptor locus and found that it has a duplication in exon 3 when CWR22 xenograft developed castration resistance. These studies have opened a new chapter for studying androgen receptor genomics in prostate cancer.

 

Epigenetics and Metabolism

        We are most interested in epigenetic regulation of tumor metabolism. Epigenetic regulation involves DNA and histone methylation as well as noncoding RNA mediated transcriptional changes which do not involve genomic sequence changes. Our lab identified the newest histone demethylase KDM8, which catalyzes the demethylation of H3K9me2 and is an oncogenic driver for several types of cancer. While it modifies histones and regulates cell cycle, it also interacts with PKM2, a gate keeper for pyruvate flux to lactate (Warburg) and translocates it to nucleus. KDM8/PKM2 complex serves as a coactivator for HIF-1a, regulating glycolytic metabolism. KDM8 associates with KDM4A, which demethylates H3K9me3/2 and H3K36me3/2. Both KDMs are coactivators of androgen receptor and regulate tumor metabolism. In the arena of noncoding RNA, our lab was the first to identify a myc coactivator long noncoding RNA, PCGEM1. PCGEM1 upregulates myc activity and facilitates the recruitment of myc to target promoters, of which a significant portion regulates genes involved in tumor metabolism. In our studies of nutritional starvation therapy of prostate cancer, we found arginine deprivation generates a completely novel type of autopohagy, which involves DNA leakage and autophagosome capturing of the broken chromatin. This is a new form of autopohagy, which we refer to it as chromatophagy. Chromatophagy involves epigenetic deregulation of mitochondria genes, leading to ROS generation and DNA damage.

 

Herpesvirology

        My lab has been a major contributor to the virology and vaccinology of Marek’s disease herpesvirus (MDV). We discovered the oncogene of MDV, meq which is a b-ZIP family protein. Deletion of Meq generates a virus which replicates well but is completely devoid of oncogenecity. This virus has shown superior protective properties as a live vaccine and is being developed as a next generation MDV vaccine. MDV is a major economic issue in poultry industry before the advent of live-virus vaccine. There are however still sporadic outbreaks of MDV in US and worldwide, caused by very virulent strain of MDV, resistant to present day vaccine. Our discovery paves the way to the development of improved vaccine. My other major discovery is the finding that retrovirus can integrate into herpesviral genome, rapidly generating new recombinant virus carrying mostly retroviral LTR. Some of the herpesvirus-retrovirus recombinants exhibit a high level of protectivity against very virulent strain of MDV. With our interest in b-ZIP protein, we extend our analysis to a new herpesviurs, KSHV (Kaposi’s sarcoma associated herpesvirus), and identified K-bZIP, a b-ZIP protein and an early gene of KSHV. K-bZIP not only serves as a transcriptional factor, mostly a repressor, but most intriguingly, it is also a E3 SUMO-ligase, the first viral SUMO ligase ever identified. Additional studies identified another gene product K-Rta as a major transcriptional activator and a SUMO-targeting E3 ubiquitin ligase. Our work thus puts sumoylation into the sharp focus of herpesvirus gene regulation and replication.

 

HIGHLIGHTS OF RECENT RESEARCH

Identification of Cancer as a Metabolic Disease and Development of Metabolism-based Therapies

fig - Kung

Cancer cells are known to have metabolic requirements different from normal cells. This metabolic adaption is to accommodate the need for rapid increase of mass and to cope with the often nutrition and oxygen-deprived tumor microenvironment. Dr. Kung’s lab found that many types of cancer are addicted to external arginine which activates mTOR, a kinase involved in regulating cell metabolism and growth. Using arginine deiminase (ADI) to deprive external arginine, tumor, but not normal, cells were killed. This treatment is distinct from conventional genotoxic therapy in that it causes cell death through lethal autophagy, a “self-eating” process. As such, it complements the apoptosis-based therapy and can overcome drug resistance. Most strikingly, the cells die from “chromatin-autophagy”, where chromatins are leaked out of the nucleus and captured by autophagosome. This study not only uncovers a novel form of autophagy but also offers new strategy for cancer treatment. ADI is currently undergoing phase III trial. (PNAS (2014); Science Signaling (2014))

 

HONORS & AWARD

NCI Merit Award (CA39207)

NCI Merit Award (CA46613)

NIH Norman Salzman Lectureship, 2012

Academia Sinica Academician, Taiwan, ROC

Auburn Community Cancer Endowment Chair in Basic Science, UC Davis 2007

Joan Oettinger Memorial Award in Lung and Cancer Research, 2006

Society of American Asian Scientists in Cancer Research (SAASCR), recipient of annual award-2006

UC Davis School of Medicine Faculty Research Award, 2005

Goodman-Blum Professor in Cancer Research, CWRU

Honorary Distinguished Fellow, NHRI, Taiwan

Faculty Research Award, American Cancer Society, 1983-1987

 

Consultantship (selected)

Cancer Research, Associate Editor, 2007-2010

Genes and Cancer, Editorial Board, 2009-present

Hormones and Cancer, Editorial Board, 2010-present

JBC Editorial Board, 2014- present

 

Study sections:

NIH Virology Study Section (2 terms), 1984 – 1988, 1991-1995

NIH Outstanding Investigator Award Review Panel, 1992, 1995

NCI Program Project Subcommittee C, 1997-2001

NIH Urology Special Review Panel, 2001, 2002

NIH Urology NIDDK Study Section, 2004-2009

NCI Oncology Fellowship, 2004, Feb 2009, June 2009

DOD Breast Cancer Research Committee, 1996,1997,1998, 2001(Chair)

DOD Ovarian Program Project Committee, Coordinator and Member, 1999

DOD Prostate Cancer Research Program, 2003

USDA Animal Health and Well-being, 2002

NCI-Cancer Center Review Panel-Subcommittee A, 2005-2009

NIH-Tumor Cell Biology Study Section, 2006, 2007, 2008, 2010

NCI Program Project Review Panel, 2008, 2009

NCI SPORE Review Panel, 2009

NIH AOIC (AIDS related opportunistic infection committee) Review Panel, 2008, 2010, 2011, 2012, 2013

NCI U54 TMEN Review Panel, 2011

NCI OIG Review panel, 2015, 2016

 

Advisory Boards:

Henry Ford Hospital Research Committee 1992 – 1996

M.D. Anderson, Brain Tumor Center, External Advisory Board, 1994, 1995,1997

Northwestern University, Hemopoiesis Program Project, External Advisory Board, 1994

DOD Center of Prostate Disease Research Advisory Committee, 1999-present

Lawrence Livermore National Laboratory, Biotechnology and Biology Program Advisory Committee, 2000-2008

UCLA Prostate Cancer SPORE External Advisory Board, 2001- present

Leukemia and Lymphoma Society, SCOR Subcommittee, 2001, 2002, 2003, 2004

City of Hope Comprehensive Cancer Center External Advisory Board, 2005-2010

Roswell Park Comprehensive Cancer Center External Advisory Board, 2004-2010

Harvard Medical School Division of Tumor Virology Advisory Committee, 2006-2007

UC Irvine Comprehensive Cancer Center External Advisory Committee, 2009-2012

Oregon Health Science University Cancer Center External Advisory, 2009-

 

 

SELECTED PUBLICATIONS

Hung CL, Wang LY, Yu YL, Chen HW, Srivastava S, Petrovics G, Kung HJ*. A long noncoding RNA connects c-myc to tumor metabolism    Poc Natl Acad Sci U S A. 111(52):18697-702      (2014).

Changou CA, Chen YR, Xing L, Yen Y, Chuang FY, Cheng RH, Bold RJ, Ann DK, Kung HJ*.    Arginine starvation-associated atypical cellular death involves mitochondrial    dysfunction,   nuclear DNA leakage, and chromatin autophagy. Proc Natl Acad Sci U S A. 111(39):14147-     52(2014).

Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, Chen CC, Izumiya Y, Yu JS, Kung     HJ*, Wang WC*.JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-    mediated glucose metabolism. Proc Natl Acad Sci U S A. 111(1):279-84 (2014)

Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung HJ, Tepper CG, Hu WS,        Coffin JM, Pathak VK. Recombinant Origin of XMRV. Science, 333(6038); 97-101. (2011)

Chen, R, Kim , O, Li, M, Ilic, D, Xioing, X, Guan, JL, Kung HJ, Chen H, Damsky, CH, Shimizu, Y and Qiu, Y. Regulation of a PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nature Cell Biol. 3:439-444, (2001)

Qiu, Y., Ravi, L, and Kung, H. J*. Requirement of erbB2 for IL6 signaling in prostate carcinoma cells. Nature, 393: 83-85 (1998)

T.W. Nilsen, P.A. Maroney, R.G. Goodwin, F. Rottman, L. Crittenden, M.A. Raines and H.-J. Kung*. c-erbB activation in ALV-induced erythroblastosis: Novel RNA processing and promoter-insertion result in the expression of an amino-truncated EGF receptor. Cell 41:719 (1985)

Y.K. Fung, W. Lewis, L.B. Crittenden and H.-J. Kung*. LTR insertion-activation of c-erbB: The molecular basis of avian leukosis virus-induced erythroblastosis. Cell 33:357 (1983)

Y.K. Fung, L.B. Crittenden, A.M. Fadley and H.-J. Kung*. Tumor induction by direct injec­tion of cloned v-src DNA into chickens. Proc. Natl. Acad. Sci. USA 80:353 (1983)

M.R. Noori-Daloii, H.-J. Kung*, R. Witter and L.B. Crittenden. The specific integration of REV proviruses in avian bursal lymphomas. Nature 294:574 (1982)

 

Lab Members

20160718_ 龔老師與研究團隊_20 (resized)

 

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