Glutaminase 2 stabilizes Dicer to repress Snail and metastasis in hepatocellular carcinoma cells

Kuo, Tsun-Cheng; Chen, Chi Kuan; Hua, Kuo Tai; Yu, Pei; Lee, Wei-Jiunn; Chen, Luyang; Jeng, Yung‐Ming; Chien, Ming‐Hsien; Kuo, Kuang Tai; Hsiao, Michael; Kuo, Min Liang

doi:10.1016/j.canlet.2016.10.012

Cited by 45 publications

(44 citation statements)

References 40 publications

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“…It has been shown that GLS2 expression is downregulated in certain types of cancer like gliomas 19 , colon 22 and HCC [20][21][22][23] . Accordingly, the nuclear concentration of GLS2 in HepG2, T98G and SH-SY5Y cancer cells, under basal conditions, is very low compared with the mitochondrial pool of this isoform.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the anti-proliferative response induced by blocking GLS or by stress due to nutrient (Gln) removal seems to occur by different mechanisms to those triggered by GLS2 overexpression. Importantly, GLS2 show anti-oncogenic roles independently of its glutaminolysis function in HCC, allowing metastasis suppression through Rac1 activation 43 and repression of the epithelial-mesenchymal transition through the Dicer-miR-34a-Snail axis 23 .…”

Section: Scientific Reports |mentioning

confidence: 99%

“…Furthermore, GLS2 was confirmed as a target gene of the tumor suppressor p53, in such a way that p53-controlled enhanced GLS2 expression was linked to a tumor-suppressive response, including reduced growth and colony formation of tumor cells 20,21 . Importantly, a recent study implicated GLS2 in miRNA regulation through Dicer stabilization, upregulation of miR-34a and repression of Snail and metastasis in hepatocellular carcinoma (HCC) cells 23 . Therefore, a strikingly different pattern, opposed to GLS, is becoming evident for GLS2 in many malignancies, but not all 3 .…”

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confidence: 99%

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Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

Oliva

Campos-Sandoval

Gómez-García

et al. 2020

Sci Rep

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Glutaminase (GA) catalyzes the first step in mitochondrial glutaminolysis playing a key role in cancer metabolic reprogramming. Humans express two types of GA isoforms: GLS and GLS2. GLS isozymes have been consistently related to cell proliferation, but the role of GLS2 in cancer remains poorly understood. GLS2 is repressed in many tumor cells and a better understanding of its function in tumorigenesis may further the development of new therapeutic approaches. We analyzed GLS2 expression in HCC, GBM and neuroblastoma cells, as well as in monkey COS-7 cells. We studied GLS2 expression after induction of differentiation with phorbol ester (PMA) and transduction with the fulllength cDNA of GLS2. In parallel, we investigated cell cycle progression and levels of p53, p21 and c-Myc proteins. Using the baculovirus system, human GLS2 protein was overexpressed, purified and analyzed for posttranslational modifications employing a proteomics LC-MS/MS platform. We have demonstrated a dual targeting of GLS2 in human cancer cells. Immunocytochemistry and subcellular fractionation gave consistent results demonstrating nuclear and mitochondrial locations, with the latter being predominant. Nuclear targeting was confirmed in cancer cells overexpressing c-Myc-and GFP-tagged GLS2 proteins. We assessed the subnuclear location finding a widespread distribution of GLS2 in the nucleoplasm without clear overlapping with specific nuclear substructures. GLS2 expression and nuclear accrual notably increased by treatment of SH-SY5Y cells with PMA and it correlated with cell cycle arrest at G2/M, upregulation of tumor suppressor p53 and p21 protein. A similar response was obtained by overexpression of GLS2 in T98G glioma cells, including downregulation of oncogene c-Myc. Furthermore, human GLS2 was identified as being hypusinated by MS analysis, a posttranslational modification which may be relevant for its nuclear targeting and/or function. Our studies provide evidence for a tumor suppressor role of GLS2 in certain types of cancer. The data imply that GLS2 can be regarded as a highly mobile and multilocalizing protein translocated to both mitochondria and nuclei. Upregulation of GLS2 in cancer cells induced an antiproliferative response with cell cycle arrest at the G2/M phase.Altered metabolism is a hallmark of cancer 1 and the term "metabolic reprogramming" has been coined to describe the whole range of metabolic abnormalities accompanying tumorigenesis and metastasis 2 . Increased

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Section: Discussionmentioning

confidence: 99%

Section: Scientific Reports |mentioning

confidence: 99%

mentioning

confidence: 99%

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Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

Oliva

Campos-Sandoval

Gómez-García

et al. 2020

Sci Rep

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“…Taken together, a growing body of evidence suggests that GLS2 displays a glioma-suppressive function, as it has also been postulated in the case of liver and colon cancers [90,92,93]. Clearly, further analysis is needed to unravel the detailed molecular mechanism underlying this phenomenon.…”

Section: Modulation Of Gasmentioning

confidence: 79%

Targeting Glutamine Addiction in Gliomas

Obara-Michlewska

Szeliga

2020

Cancers

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The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

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“…[141][142][143] Moreover, miR-34a affected the non-glutamate decomposition of glutaminase 2 (GLS2) through the Dicer-miR-34a-Snail1 pathway, which promotes miR-34a maturation by interacting with Dicer and stabilizing Dicer. 144 Up-regulated miR-34a inhibited EMT by suppressing Snail1 expression, ultimately inhibiting the migration and invasion of HCC. LncRNA-MUF, acting as the competitive endogenous RNA of miR-34a, restored Snail1 and promoted EMT, thus participated in the metastasis and invasion of HCC.…”

Section: The Role Of Mir-34a In the Migration And Invasion Of Hccmentioning

confidence: 99%

<p>A Systemic Review on the Regulatory Roles of miR-34a in Gastrointestinal Cancer</p>

Kong¹,

Wang²

2020

OTT

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MicroRNAs (miRNAs) are a class of endogenous non-coding single-stranded small-molecule RNAs that regulate gene expression by repressing target messenger RNA (mRNA) translation or degrading mRNA. miR-34a is one of the most important miRNAs participating in various physiological and pathological processes. miR-34a is abnormally expressed in a variety of tumors. The roles of miR-34a in gastrointestinal cancer (GIC) draw lots of attention. Numerous studies have demonstrated that dysregulated miR-34a is closely related to the proliferation, differentiation, migration, and invasion of tumor cells, as well as the diagnosis, prognosis, treatment, and chemo-resistance of tumors. Thus, we systematically reviewed the abnormal expression and regulatory roles of miR-34a in GICs including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC). It may provide a profile of versatile roles of miR-34a in GICs.

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Glutaminase 2 stabilizes Dicer to repress Snail and metastasis in hepatocellular carcinoma cells

Cited by 45 publications

References 40 publications

Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

Targeting Glutamine Addiction in Gliomas

<p>A Systemic Review on the Regulatory Roles of miR-34a in Gastrointestinal Cancer</p>

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