Nuclear receptors are critical regulators of liver diseases. Metabolic rewiring in cancer is tightly connected to changes at the epigenetic level, and the interaction of metabolism and epigenetics constitutes a new avenue of cancer biology. Exposure to high concentrations of inorganic arsenic increases the risk of liver cancer. However, the mechanisms of arsenic toxicity remain less well understood. Our past studies have established a feedback regulation of DNA methyltransferase (Dnmt) expression by nuclear receptor small heterodimer partner (SHP). Using unbiased genomic screening approaches and SHP-/- mice, my laboratory recently uncovered the mitochondrial protein pyruvate dehydrogenase kinase 4 (PDK4) as a new putative tumor suppressor that mediates epigenetic control of HCC metabolic reprogramming. The overall objective is to elucidate a novel crosstalk between PDK4 and arsenic in HCC cell metabolism and growth. The central hypothesis is that PDK4 serves as a key nutrient sensor downstream of the mammalian target of rapamycin (mTOR) pathway, acting as a double- edged sword by inhibiting glutamate dehydrogenase (GDH) in glutaminolysis and pyruvate dehygrogenase (PDH) in TCA cycle, two central pathways that fuel cancer metabolism. Furthermore, we postulate that arsenic promotes HCC growth by enhancing epigenetic silencing of PDK4 through Dnmts.
Specific Aims : 1) Determine nutrient-mediated PDK4 expression in modulation of mitochondrial glutaminolysis; 2) Determine metabolic reprogramming and altered mitochondrial function caused by PDK4; and 3) Determine the effect of arsenic on epigenetic regulation of PDK4 and hepatocarcinogenesis. The proposed experiments build on our long-standing experience in studying nuclear receptor regulation of HCC development and the appropriate use of knockout mouse models. Key reagents and methodologies required for the study are in hand, including stable PDK4 overexpression and knockdown HCC cells, an orthotopic transplanted liver cancer model, and PDK4-/- mice. High throughout transcriptomics (RNA-seq), metabolomics (GC/MS), genomics (MeDIP), and proteomics (LC-MS/MS) analyses will be employed for the proposed study, which makes the proposal comprehensive, yet feasible. Thus this application is innovative both conceptually and in the implementation of experimental approaches. This study links the emerging, very competitive field of nutrient mediated cancer cell metabolism with epigenetic regulation, and as such is expected to substantially advance our basic understanding of HCC. In addition, the PI has assembled an outstanding research team with appropriate expertise, including the areas of proteomics (Schwartz, Lam), cancer cell metabolism (Ayer), metabolomics (Cox), and environmental toxicants (Delker). The combined expertise of the PI and her collaborators further ensures the success of this project.

Public Health Relevance

Liver disease, in particular hepatocellular carcinoma (HCC), is an important and growing cause of morbidity and mortality in the United States and there is a great need to identify new tumor suppressors for the early diagnosis, treatment or prevention of HCC. Arsenic is a known hepatocarcinogen but the mechanisms of arsenic toxicity remain poorly understood, especially in the context of liver cancer cell metabolism. The proposed research will determine the crosstalk between a new tumor suppressor PDK4 and arsenic in HCC, which is relevant to the mission of NIEHS to discover how the environment affects people in order to promote healthier lives.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES025909-03
Application #
9278176
Study Section
Special Emphasis Panel (ZRG1-SIEE-C (01)Q)
Program Officer
Reinlib, Leslie J
Project Start
2015-07-15
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$355,500
Indirect Cost
$130,500
Name
University of Connecticut
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Wu, Jianguo; Zhao, Yulan; Park, Young-Ki et al. (2018) Loss of PDK4 switches the hepatic NF-?B/TNF pathway from pro-survival to pro-apoptosis. Hepatology :
Hollister, Kristin; Kusumanchi, Praveen; Ross, Ruth Ann et al. (2018) Levels of circulating follicular helper T cells, T helper 1 cells, and the prognostic significance of soluble form of CD40 ligand on survival in patients with alcoholic cirrhosis. Liver Res 2:52-59
Chang, Binxia; Hao, Shuli; Zhang, Longyu et al. (2018) Association Between Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism and Alcoholic Liver Disease. Am J Med Sci 356:10-14
Liu, Chune; Yang, Zhihong; Wu, Jianguo et al. (2018) Long noncoding RNA H19 interacts with polypyrimidine tract-binding protein 1 to reprogram hepatic lipid homeostasis. Hepatology 67:1768-1783
Tran, Melanie; Wang, Li (2017) Preserving LXR by inhibiting T39: A step closer to treating atherosclerosis and steatohepatitis? Hepatology 65:741-744
Zhao, Yulan; Yang, Zhihong; Wu, Jianguo et al. (2017) High-mobility-group protein 2 regulated by microRNA-127 and small heterodimer partner modulates pluripotency of mouse embryonic stem cells and liver tumor initiating cells. Hepatol Commun 1:816-830
Yang, Zhihong; Ross, Ruth A; Zhao, Shi et al. (2017) LncRNA AK054921 and AK128652 are potential serum biomarkers and predictors of patient survival with alcoholic cirrhosis. Hepatol Commun 1:513-523
Yu, Ai-Ming; Ingelman-Sundberg, Magnus; Cherrington, Nathan J et al. (2017) Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta Pharm Sin B 7:241-248
Zhang, Li; Yang, Zhihong; Trottier, Jocelyn et al. (2017) Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay. Hepatology 65:604-615
Song, Yongfeng; Liu, Chune; Liu, Xia et al. (2017) H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule. Hepatology 66:1183-1196

Showing the most recent 10 out of 24 publications