SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape

Zhen Wang; Ruofei Dai; Li Kang; Huan Yang; Zhaosu Chen; Jianzhong He; Lei Shu; Yiting Zhong; Yunfeng Zhang; Zhengyi Hua; Yuanyong Huang; Yuhan Jiang; Jiwen Li; Liyan Xu; Fei Lan; Shu Hai Lin; Jiemin Wong

doi:10.1038/s41467-025-63591-z

SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape

Zhen Wang, Ruofei Dai, Li Kang, Huan Yang, Zhaosu Chen, Jianzhong He, Lei Shu, Yiting Zhong, Yunfeng Zhang, Zhengyi Hua, Yuanyong Huang, Yuhan Jiang, Jiwen Li, Liyan Xu, Fei Lan, Shu Hai Lin, Jiemin Wong

School of Life Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	8190
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-63591-z
State	Published - Dec 2025

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Wang, Z., Dai, R., Kang, L., Yang, H., Chen, Z., He, J., Shu, L., Zhong, Y., Zhang, Y., Hua, Z., Huang, Y., Jiang, Y., Li, J., Xu, L., Lan, F., Lin, S. H., & Wong, J. (2025). SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape. Nature Communications, 16(1), Article 8190. https://doi.org/10.1038/s41467-025-63591-z

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title = "SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape",

abstract = "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.",

author = "Zhen Wang and Ruofei Dai and Li Kang and Huan Yang and Zhaosu Chen and Jianzhong He and Lei Shu and Yiting Zhong and Yunfeng Zhang and Zhengyi Hua and Yuanyong Huang and Yuhan Jiang and Jiwen Li and Liyan Xu and Fei Lan and Lin, \{Shu Hai\} and Jiemin Wong",

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doi = "10.1038/s41467-025-63591-z",

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T1 - SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape

AU - Wang, Zhen

AU - Dai, Ruofei

AU - Kang, Li

AU - Yang, Huan

AU - Chen, Zhaosu

AU - He, Jianzhong

AU - Shu, Lei

AU - Zhong, Yiting

AU - Zhang, Yunfeng

AU - Hua, Zhengyi

AU - Huang, Yuanyong

AU - Jiang, Yuhan

AU - Li, Jiwen

AU - Xu, Liyan

AU - Lan, Fei

AU - Lin, Shu Hai

AU - Wong, Jiemin

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-025-63591-z

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SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

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ER -

SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape

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