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.

中文翻译：

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NRF2 / ACSS2轴介导饮酒对食管鳞状细胞癌的代谢作用。

饮酒是食管鳞状细胞癌（ESCC）发展的主要危险因素。但是，酒精相关的ESCC的分子机制仍然知之甚少。ESCC中最常见的突变基因之一是核因子类红细胞2（NFE2L2或NRF2），它是调节氧化应激反应和药物排毒的关键转录因子。但是，当NRF2在癌细胞中过度活跃时，会导致代谢重编程，细胞增殖，化学放射抗性和不良预后。在这项研究中，发现过度活跃的NRF2在ESCC细胞和小鼠食道中上调了乙酰辅酶A合成酶短链家族成员2（ACSS2），一种将乙酸转化为乙酰辅酶A的酶。我们还显示，敲低NRF2或ACSS2会导致ACSS2表达下降，反过来，无论有无乙醇暴露，均可降低乙酰辅酶A和ATP的含量。另外，乙醇暴露增强了ESCC细胞中脂质的合成。此外，我们观察到由于乙醇的NRF2或ACSS2状态，ESCC细胞的代谢特征发生了变化。我们进一步表明，ACSS2有助于暴露于乙醇的NRF2high ESCC细胞的侵袭能力。总之，NRF2 / ACSS2轴介导饮酒对ESCC的代谢作用。我们进一步表明，ACSS2有助于暴露于乙醇的NRF2high ESCC细胞的侵袭能力。总之，NRF2 / ACSS2轴介导饮酒对ESCC的代谢作用。我们进一步表明，ACSS2有助于暴露于乙醇的NRF2high ESCC细胞的侵袭能力。总之，NRF2 / ACSS2轴介导饮酒对ESCC的代谢作用。