2. Academic Validation
  3. Enhanced monoacylglycerol lipolysis by ABHD6 promotes NSCLC pathogenesis

Enhanced monoacylglycerol lipolysis by ABHD6 promotes NSCLC pathogenesis

  • EBioMedicine. 2020 Mar;53:102696. doi: 10.1016/j.ebiom.2020.102696.
Zhiyuan Tang 1,  Hao Xie 2,  Christoph Heier 2,  Jianfei Huang 3,  Qiuling Zheng 4,  Thomas O Eichmann 5,  Gabriele Schoiswohl 2,  Jun Ni 6,  Rudolf Zechner 2,  Songshi Ni 7,  Haiping Hao 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong 226001, China; Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 2 Institute of Molecular Biosciences, University of Graz, Graz 8010, Austria.
  • 3 Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong 226001, China.
  • 4 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 5 Institute of Molecular Biosciences, University of Graz, Graz 8010, Austria; Center for Explorative Lipidomics, BioTechMed-Graz, Graz 8010, Austria.
  • 6 Department of Rehabilitation, The First Affiliated Hospital of Fujian Medical University, Fujian 350000, China.
  • 7 Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China. Electronic address: [email protected].
  • 8 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
PMID: 32143183 DOI: 10.1016/j.ebiom.2020.102696
Abstract

Background: Tumor cells display metabolic changes that correlate with malignancy, including an elevated hydrolysis of monoacylglycerol (MAG) in various Cancer types. However, evidence is absent for the relationship between MAG lipolysis and NSCLC.

Methods: MAG hydrolase activity assay, migration, invasion, proliferation, lipids quantification, and transactivation assays were performed in vitro. Tumor xenograft studies and lung metastasis assays were examined in vivo. The correlations of MAGL/ABHD6 expression in cancerous tissues with the clinicopathological characteristics and survival of NSCLC patients were validated.

Findings: ABHD6 functions as the primary MAG Lipase and an oncogene in NSCLC. MAG hydrolase activities were more than 11-fold higher in cancerous lung tissues than in paired non-cancerous tissues derived from NSCLC patients. ABHD6, instead of MAGL, was significantly associated with advanced tumor node metastasis (TNM) stage (HR, 1.382; P = 0.004) and had a negative impact on the overall survival of NSCLC patients (P = 0.001). ABHD6 silencing reduced migration and invasion of NSCLC cells in vitro as well as metastatic seeding and tumor growth in vivo. Conversely, ectopic overexpression of ABHD6 provoked the pathogenic potential. ABHD6 blockade significantly induced intracellular MAG accumulation which activated PPARα/γ signaling and inhibited Cancer pathophysiology.

Interpretation: The present study provide evidence for a previously uncovered pro-oncogenic function of ABHD6 in NSCLC, with the outlined metabolic mechanisms shedding LIGHT on new potential strategies for Anticancer therapy. FUND: This work was supported by the Project for Major New Drug Innovation and Development (2015ZX09501010 and 2018ZX09711001-002-003).

Keywords

ABHD6; Aggressiveness; MAG; NSCLC.

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