Wang Zhen, Dai Ruofei, Kang Li, Yang Huan, Chen Zhaosu, He Jianzhong, Shu Lei, Zhong Yiting, Zhang Yunfeng, Hua Zhengyi, Huang Yuanyong, Jiang Yuhan, Li Jiwen, Xu Liyan, Lan Fei, Lin Shu-Hai, Wong Jiemin
Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Nat Commun. 2025 Sep 2;16(1):8190. doi: 10.1038/s41467-025-63591-z.
SOX2 is a potent oncodriver for various squamous cancers, but the underlying mechanism is largely unknown. Here we uncover a role of SOX2 in promoting global histone acetylation in esophageal squamous cancer cells (ESCCs). Mechanistic studies reveal that SOX2 promotes global histone acetylation in an AKT-independent manner, and does so by promoting histone acetylation at both SOX2 binding and non-SOX2 binding sites, and accounts for the formation of about half of the super-enhancers. Combined metabolic and transcriptional analyses reveal two mechanisms by which SOX2 enhances global histone acetylation: promoting the expression of multiple histone acetyltransferases and reducing acetyl-CoA consuming fatty acid synthesis in part by repressing the expression of ACSL5. Finally, SOX2 expression correlates negatively with ACSL5 and positively with histone acetylation in clinical esophageal squamous tumors. Altogether, our study uncovers a role of SOX2 in reprogramming lipid metabolism and driving histone hyperacetylation and super-enhancer function, providing mechanistic insights of SOX2 acting as a potent oncodriver.
SOX2是多种鳞状细胞癌的一种强大的致癌驱动因子，但其潜在机制在很大程度上尚不清楚。在此，我们揭示了SOX2在促进食管鳞状癌细胞（ESCC）中整体组蛋白乙酰化方面的作用。机制研究表明，SOX2以不依赖AKT的方式促进整体组蛋白乙酰化，其通过促进SOX2结合位点和非SOX2结合位点的组蛋白乙酰化来实现这一点，并约占超级增强子形成的一半。综合代谢和转录分析揭示了SOX2增强整体组蛋白乙酰化的两种机制：促进多种组蛋白乙酰转移酶的表达，并通过部分抑制ACSL5的表达来减少消耗乙酰辅酶A的脂肪酸合成。最后，在临床食管鳞状肿瘤中，SOX2表达与ACSL5呈负相关，与组蛋白乙酰化呈正相关。总之，我们的研究揭示了SOX2在重编程脂质代谢以及驱动组蛋白高乙酰化和超级增强子功能方面的作用，为SOX2作为一种强大的致癌驱动因子提供了机制性见解。
