Division of Gastroenterology and Hepatology, Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, 10021, USA; Department of Gastroenterology, Xiangya Hospital of Central South University, Hunan, China.
Division of Gastroenterology and Hepatology, Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, 10021, USA; Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Cancer Lett. 2023 Jul 1;565:216210. doi: 10.1016/j.canlet.2023.216210. Epub 2023 May 5.
Cancer cells use acetate to support the higher demand for energy and lipid biosynthesis during uncontrolled cell proliferation, as well as for acetylation of regulatory proteins. Acyl-CoA thioesterase 12 (Acot12) is the enzyme that hydrolyzes acetyl-CoA to acetate in liver cytosol and is downregulated in hepatocellular carcinoma (HCC). A mechanistic role for Acot12 in hepatocarcinogenesis was assessed in mice in response to treatment with diethylnitrosamine(DEN)/carbon tetrachloride (CCl) administration or prolonged feeding of a diet that promotes non-alcoholic steatohepatitis (NASH). Relative to controls, Acot12 mice exhibited accelerated liver tumor formation that was characterized by the hepatic accumulation of glycerolipids, including lysophosphatidic acid (LPA), and that was associated with reduced Hippo signaling and increased yes-associated protein (YAP)-mediated transcriptional activity. In Acot12 mice, restoration of hepatic Acot12 expression inhibited hepatocarcinogenesis and YAP activation, as did knockdown of hepatic YAP expression. Excess LPA produced due to deletion of Acot12 signaled through LPA receptors (LPARs) coupled to Gα12/13 subunits to suppress YAP phosphorylation, thereby promoting its nuclear localization and transcriptional activity. These findings identify a protective role for Acot12 in suppressing hepatocarcinogenesis by limiting biosynthesis of glycerolipids including LPA, which preserves Hippo signaling.
癌细胞在不受控制的细胞增殖过程中会利用乙酸盐来支持对能量和脂质生物合成的更高需求，以及用于调节蛋白的乙酰化。酰基辅酶 A 硫酯酶 12（Acot12）是一种在肝胞质溶胶中将乙酰辅酶 A 水解为乙酸盐的酶，在肝细胞癌（HCC）中下调。在对二乙基亚硝胺（DEN）/四氯化碳（CCl）给药或长期喂养促进非酒精性脂肪性肝炎（NASH）的饮食的小鼠中评估了 Acot12 在肝癌发生中的机制作用。与对照相比，Acot12 小鼠表现出加速的肝肿瘤形成，其特征是肝甘油脂质的积累，包括溶血磷脂酸（LPA），并且与 Hippo 信号的降低和 yes 相关蛋白（YAP）介导的转录活性的增加相关。在 Acot12 小鼠中，恢复肝 Acot12 表达抑制了肝癌发生和 YAP 激活，肝 YAP 表达的敲低也是如此。由于 Acot12 的缺失而产生的过量 LPA 通过与 Gα12/13 亚基偶联的 LPA 受体（LPAR）发出信号，抑制 YAP 磷酸化，从而促进其核定位和转录活性。这些发现确定了 Acot12 在通过限制包括 LPA 在内的甘油脂质生物合成来抑制肝癌发生中的保护作用，从而维持 Hippo 信号。
