Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer with high mortality in the United States. Tumor suppressor p53 plays a crucial role in tumor prevention, including HCC, through its regulation of cell cycle arrest, apoptosis and senescence. Recent studies suggested a novel function for p53 in tumor suppression, i.e. p53 regulates energy metabolism. As a hallmark of tumor cells, metabolic changes (e.g. Warburg effect) were recently suggested to be a key contributor to tumorigenesis and a potential target for tumor therapy. We identified a novel p53 target gene, the mitochondrial glutaminase 2 (GLS2), a gene encoding an enzyme involved in mitochondrial respiration, which provides a direct link for p53 and metabolism. Strikingly, our data from a limited number of samples show that GLS2 expression is absent or significantly decreased (by over 20-fold) in almost all of the HCC specimens we analyzed as compared with the adjacent normal or cirrhotic liver tissues. Our preliminary data further suggest that GLS2 may suppress tumorigenesis and regulates energy metabolism. Based on our results, we hypothesize that GLS2 may play a critical role in tumor suppression through its regulation of metabolism. In this proposed study we plan to: 1) determine the GLS2 expression in additional 100 HCC specimens to establish the loss of GLS2 as a common and specific event for HCC which could be a potential tumor biomarker. 2) Test the hypothesis that loss of GLS2 epxression promotes tumorigenesis while restoration of GLS2 expression inhibits liver tumorigenesis in nude mice. 3) Identify mechanisms for GLS2 in tumor suppression. In particular, we will determine GLS2's role in regulation of energy metabolism, stress responses and antioxidantion. 4) Identify mechanisms underlying the loss of the GLS2 expression in HCC. In response to RFA (PA-08-243) entitled """"""""Etiology, Prevention, and Treatment of Hepatocellular Carcinoma"""""""", this proposed study will greatly increase our understanding of the mechanisms for liver tumorigenesis and expand our understanding of mechanisms of p53 in tumor suppression, especially the role of metabolic changes in tumorigenesis and the role of reversing metabolic changes in tumor therapy. It is our anticipation that this study will have direct potential to provide GLS2 as a novel tumor biomarker and therapeutic target for tumor therapy, especially for HCC.

Public Health Relevance

In this proposed study we will study the role and mechanisms of GLS2 gene in tumor suppression. This study will greatly increase our understanding of the molecular mechanisms for tumorigenesis, especially the role of metabolic changes in tumor initiation and progression. This study will have direct potential to provide GLS2 as a novel tumor biomarker for tumor diagnosis and therapeutic target for tumor therapy, especially for liver cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA143204-05
Application #
8699974
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Spalholz, Barbara A
Project Start
2010-02-01
Project End
2014-11-30
Budget Start
2013-07-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$222,575
Indirect Cost
$82,591
Name
Rbhs -Cancer Institute of New Jersey
Department
Type
DUNS #
078728091
City
New Brunswick
State
NJ
Country
United States
Zip Code
08903
Zhang, Cen; Liu, Juan; Huang, Grace et al. (2016) Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev 30:1956-70
Yue, Xuetian; Zhao, Yuhan; Huang, Grace et al. (2016) A novel mutant p53 binding partner BAG5 stabilizes mutant p53 and promotes mutant p53 GOFs in tumorigenesis. Cell Discov 2:16039
Zhang, Cen; Liu, Juan; Tan, Chunwen et al. (2016) microRNA-1827 represses MDM2 to positively regulate tumor suppressor p53 and suppress tumorigenesis. Oncotarget 7:8783-96
Zhang, Cen; Liu, Juan; Zhao, Yuhan et al. (2016) Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis. Elife 5:e10727
Yue, Xuetian; Zhao, Yuhan; Liu, Juan et al. (2015) BAG2 promotes tumorigenesis through enhancing mutant p53 protein levels and function. Elife 4:
Liu, Juan; Zhang, Cen; Wu, Rui et al. (2015) RRAD inhibits the Warburg effect through negative regulation of the NF-κB signaling. Oncotarget 6:14982-92
Liu, Juan; Zhang, Cen; Hu, Wenwei et al. (2015) Tumor suppressor p53 and its mutants in cancer metabolism. Cancer Lett 356:197-203
Zhao, Y; Zhang, C; Yue, X et al. (2015) Pontin, a new mutant p53-binding protein, promotes gain-of-function of mutant p53. Cell Death Differ 22:1824-36
Zhang, Cen; Liu, Juan; Wang, Xiaolong et al. (2015) The regulation of the p53/MDM2 feedback loop by microRNAs. RNA Dis 2:e502
Liu, Juan; Zhang, Cen; Feng, Zhaohui (2014) Tumor suppressor p53 and its gain-of-function mutants in cancer. Acta Biochim Biophys Sin (Shanghai) 46:170-9

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