Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, U.S.A.
Integrated Biosciences PhD Program, North Carolina Central University, Durham, NC 27707, U.S.A.
Biochem J. 2020 Aug 28;477(16):3075-3089. doi: 10.1042/BCJ20200452.
Alcohol drinking is a leading risk factor for the development of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanisms of alcohol-associated ESCC remain poorly understood. One of the most commonly mutated genes in ESCC is nuclear factor erythroid 2 like 2 (NFE2L2 or NRF2), which is a critical transcription factor regulating oxidative stress response and drug detoxification. When NRF2 is hyperactive in cancer cells, however, it leads to metabolic reprogramming, cell proliferation, chemoradioresistance, and poor prognosis. In this study, hyperactive NRF2 was found to up-regulate acetyl-CoA synthetase short-chain family members 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in ESCC cells and mouse esophagus. We also showed that knockdown of NRF2 or ACSS2 led to decreased ACSS2 expression, which in turn reduced the levels of acetyl-CoA and ATP with or without ethanol exposure. In addition, ethanol exposure enhanced lipid synthesis in ESCC cells. Moreover, we observed a change in the metabolic profile of ESCC cells exposed to ethanol as a result of their NRF2 or ACSS2 status. We further showed that ACSS2 contributed to the invasive capability of NRF2high ESCC cells exposed to ethanol. In conclusion, the NRF2/ACSS2 axis mediates the metabolic effect of alcohol drinking on ESCC.
饮酒是食管鳞状细胞癌（ESCC）发展的主要危险因素。然而，酒精相关的 ESCC 的分子机制仍知之甚少。ESCC 中最常见的突变基因之一是核因子红细胞 2 样 2（NFE2L2 或 NRF2），它是一种关键的转录因子，调节氧化应激反应和药物解毒。然而，当 NRF2 在癌细胞中过度活跃时，它会导致代谢重编程、细胞增殖、化疗和放疗耐药以及预后不良。在这项研究中，发现过度活跃的 NRF2 会在上皮细胞和小鼠食管中上调乙酰辅酶 A 合成酶短链家族成员 2（ACSS2），该酶将乙酸转化为乙酰辅酶 A。我们还表明，敲低 NRF2 或 ACSS2 会导致 ACSS2 表达减少，这反过来又降低了乙酰辅酶 A 和 ATP 的水平，无论是否暴露于乙醇。此外，乙醇暴露会增强 ESCC 细胞中的脂质合成。此外，我们观察到由于 NRF2 或 ACSS2 状态的变化，暴露于乙醇的 ESCC 细胞的代谢谱发生了变化。我们进一步表明，ACSS2 有助于 NRF2 高表达的 ESCC 细胞在暴露于乙醇时的侵袭能力。总之，NRF2/ACSS2 轴介导了饮酒对 ESCC 的代谢作用。
