SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape
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.
Authors
- Jiwen Li (ORCID: https://orcid.org/0000-0002-1332-4763)
- Yuanyong Huang
- Zhaosu Chen
- Li‐Yan Xu (ORCID: https://orcid.org/0000-0002-1618-4292)
- Jianzhong He (ORCID: https://orcid.org/0000-0003-1256-472X)
- Huan Yang (ORCID: https://orcid.org/0000-0001-8511-2172)
- Zichun Hua (ORCID: https://orcid.org/0000-0001-7962-0402)
- Shuhai Lin (ORCID: https://orcid.org/0000-0002-4782-5320)
- Jiemin Wong (ORCID: https://orcid.org/0000-0002-5311-842X)
- Ruofei Dai
- Yunfeng Zhang (ORCID: https://orcid.org/0000-0003-1078-0752)
- Zhen Wang (ORCID: https://orcid.org/0000-0002-1215-1661)
- Kang Li (ORCID: https://orcid.org/0009-0006-7318-2185)
- Yi Zhong (ORCID: https://orcid.org/0000-0002-9309-3407)
- Lei Shu (ORCID: https://orcid.org/0000-0002-6326-5730)
- Fei Lan (ORCID: https://orcid.org/0000-0002-8559-7146)
- Yuhan Jiang (ORCID: https://orcid.org/0009-0005-4927-4875)
Institutions
- Xiamen University (CN)
- Fudan University (CN)
- Shantou University (CN)
- Cancer Hospital of Shantou University Medical College (CN)
- Shandong Provincial Hospital (CN)
- Shantou University Medical College (CN)
- Zhongshan Hospital (CN)
- Shandong First Medical University (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-02
- DOI
- https://doi.org/10.1038/s41467-025-63591-z
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Chinese Academy of Medical Sciences
- National Key Research and Development Program of China