Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis

eLife, Jan 2016

Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors (GEFs), which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53's function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://elifesciences.org/content/elife/early/2016/01/11/eLife.10727.full.pdf

Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis

Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis Cen Zhang Juan Liu Yuhan Zhao Xuetian Yue Yu Zhu Xiaolong Wang Hao Wu Felix Blanco Shaohua Li Gyan Bhanot Bruce G Haffty Wenwei Hu Zhaohui Feng This PDF is the version of the article that was accepted for publication after peer review. Fully formatted HTML, PDF, and XML versions will be made available after technical processing, editing, and proofing. - Stay current on the latest in life science and biomedical research from eLife. Sign up for alerts at elife.elifesciences.org Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA. 2 Department of Surgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA. 3 Department of Molecular Biology, Biochemistry & Physics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. 4 Co-first authors 5 Correspondence: W.H. (email: ) or Z.F. (email: ) Running Title: GLS2 inhibits Rac1 to suppress metastasis Abstract Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors (GEFs), which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53’s function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis. Introduction Metabolic changes are a hallmark of cancer cells (Berkers et al., 2013; Cairns et al., 2011; Ward and Thompson, 2012). Increased glutamine metabolism (glutaminolysis) has been recognized as a key metabolic change in cancer cells, along with increased aerobic glycolysis (the Warburg effect) (Berkers et al., 2013; Cairns et al., 2011; DeBerardinis et al., 2007; Hensley et al., 2013; Ward and Thompson, 2012). Glutamine is the most abundant amino acid in human plasma (Hensley et al., 2013). Glutamine catabolism starts with the conversion of glutamine to glutamate, which is converted to α-ketoglutarate for further metabolism in the tricarboxylic acid (TCA) cycle. Recent studies have shown that increased glutamine metabolism plays a critical role in supporting the high proliferation and survival of cancer cells by providing pools of the TCA cycle intermediates, as well as the biosynthesis of proteins, lipids, and nucleotides (Berkers et al., 2013; Cairns et al., 2011; DeBerardinis et al., 2007; Hensley et al., 2013; Ward and Thompson, 2012). Glutaminase (GLS) is the initial enzyme in glutamine metabolism, which catalyzes the hydrolysis of glutamine to glutamate in cells. Two genes encode glutaminases in human cells: GLS1 (also known as kidney-type glutaminase), and GLS2 (also known as liver-type glutaminase). GLS1 and GLS2 proteins exhibit a high degree of amino acid sequence similarity, particularly in their glutaminase core domains. While GLS1 and GLS2 both function as glutaminase enzymes in glutamine metabolism, recent studies show that they have very different functions in tumorigenesis. GLS1 is ubiquitously expressed in various tissues, and its expression can be induced by the oncogene MYC (Gao et al., 2009). GLS1 is frequently activated and/or overexpressed in various types of cancer, including hepatocellular carcinoma (HCC) (Gao et al., 2009; Thangavelu et al., 2012; Wang et al., 2010; Xiang et al., 2015). GLS1 has been reported to promote tumorigenesis in different types 3 of cancer, including HCC, which is mainly attributable to its glutaminase activity and its role in promoting glutamine metabolism (Gao et al., 2009; Thangavelu et al., 2012; Wang et al., 2010; Xiang et al., 2015). In contrast, GLS2 is specifically expressed in only a few tissues, including the liver tissue. Recent studies including ours have shown that GLS2 is a novel target gene of the tumor suppressor p53. GLS2 is transcriptionally up-regulated by p53 and mediates p53’s regulation of mitochondrial function and anti-oxidant defense in cells (Hu et al., 2010; Suzuki et al., 2010). Considering the critical role of p53 and its pathway in tumor suppressio (...truncated)


This is a preview of a remote PDF: http://elifesciences.org/content/elife/early/2016/01/11/eLife.10727.full.pdf

Cen Zhang, Juan Liu, Yuhan Zhao, Xuetian Yue, Yu Zhu, Xiaolong Wang, Hao Wu, Felix Blanco, Shaohua Li, Gyan Bhanot, Bruce G Haffty, Wenwei Hu, Zhaohui Feng. Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis, eLife, 2016, DOI: 10.7554/eLife.10727