Zagani Rachid, El-Assaad Wissal, Gamache Isabelle, Teodoro Jose G
Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.
Department of Biochemistry, McGill University, Montréal, QC, Canada.
Oncotarget. 2015 Sep 29;6(29):28282-95. doi: 10.18632/oncotarget.5061.
The G0/G1 switch gene 2 (G0S2) is methylated and silenced in a wide range of human cancers. The protein encoded by G0S2 is an endogenous inhibitor of lipid catabolism that directly binds adipose triglyceride lipase (ATGL). ATGL is the rate-limiting step in triglyceride metabolism. Although the G0S2 gene is silenced in cancer, the impact of ATGL in the growth and survival of cancer cells has never been addressed. Here we show that ectopic expression of G0S2 in non-small cell lung carcinomas (NSCL) inhibits triglyceride catabolism and results in lower cell growth. Similarly, knockdown of ATGL increased triglyceride levels, attenuated cell growth and promoted apoptosis. Conversely, knockdown of endogenous G0S2 enhanced the growth and invasiveness of cancer cells. G0S2 is strongly induced in acute promyelocytic leukemia (APL) cells in response to all trans retinoic acid (ATRA) and we show that inhibition of ATGL in these cells by G0S2 is required for efficacy of ATRA treatment. Our data uncover a novel tumor suppressor mechanism by which G0S2 directly inhibits activity of a key intracellular lipase. Our results suggest that elevated ATGL activity may be a general property of many cancer types and potentially represents a novel target for chemotherapy.
G0/G1转换基因2（G0S2）在多种人类癌症中发生甲基化并被沉默。G0S2编码的蛋白质是脂质分解代谢的内源性抑制剂，可直接结合脂肪甘油三酯脂肪酶（ATGL）。ATGL是甘油三酯代谢的限速步骤。尽管G0S2基因在癌症中沉默，但ATGL对癌细胞生长和存活的影响从未得到探讨。在此我们表明，非小细胞肺癌（NSCL）中G0S2的异位表达抑制甘油三酯分解代谢并导致细胞生长减缓。同样，敲低ATGL会增加甘油三酯水平，减弱细胞生长并促进细胞凋亡。相反，敲低内源性G0S2会增强癌细胞的生长和侵袭性。在急性早幼粒细胞白血病（APL）细胞中，全反式维甲酸（ATRA）可强烈诱导G0S2表达，并且我们表明G0S2在这些细胞中抑制ATGL对于ATRA治疗的疗效是必需的。我们的数据揭示了一种新的肿瘤抑制机制，即G0S2直接抑制关键细胞内脂肪酶的活性。我们的结果表明，ATGL活性升高可能是许多癌症类型的普遍特征，并且可能代表化疗的新靶点。
