YEATS4 reads histone crotonylation to promote fatty acid metabolism and cancer cell stemness
How histone lysine crotonylation (Kcr) is read and interpreted remains to be elucidated. We report here that YEATS4, a potential breast cancer driver identified recently by two independent genome-wide association studies, is a reader of H3K14cr. Integrative metabolomic, epigenomic, and transcriptomic analyses reveal that H3K14cr reading by YEATS4 is associated with a shift of cellular metabolic profile and transcription activation of a cohort of genes, including CD36, CPT1A, and ACOX1, that are critically involved in the uptake and metabolism of fatty acids. High expression of YEATS4 fortifies fatty acid metabolism, enhances self-renewal and growth of ALDH<sup>+</sup> breast cancer stem cells, and is correlated with poor prognosis of breast cancer patients, especially the ER<sup>+</sup> subtype. Our work uncovers YEATS4 as an "amplifier" in the feedforward circuit of histone crotonylation and lipid metabolism underlying the stemness and cell proliferation, supporting the pursuit of YEATS4 as a potential target for breast cancer intervention.
Authors
- Chengying Zhang (ORCID: https://orcid.org/0009-0000-4173-0753)
- Mengyang Geng
- Yuqing Wu (ORCID: https://orcid.org/0000-0003-3140-166X)
- Ge Wu (ORCID: https://orcid.org/0000-0002-8971-1911)
- Jianying Liu (ORCID: https://orcid.org/0000-0003-3855-8280)
- Dan Zhao (ORCID: https://orcid.org/0000-0003-0195-6031)
- Yongfeng Shang (ORCID: https://orcid.org/0000-0001-5050-7625)
- Xin Wu (ORCID: https://orcid.org/0000-0003-2326-3404)
- Haitao Li (ORCID: https://orcid.org/0000-0001-6741-293X)
- Yizhou Wang (ORCID: https://orcid.org/0000-0002-9378-745X)
- Jing Liang (ORCID: https://orcid.org/0000-0002-7003-7920)
- Leyi Qin
- Zijun Peng
- Zhimin Lu (ORCID: https://orcid.org/0000-0002-4123-7050)
- Yilei Ma (ORCID: https://orcid.org/0009-0009-3401-1561)
- Huajing Yu (ORCID: https://orcid.org/0000-0002-8028-6146)
- Yue Wang (ORCID: https://orcid.org/0000-0003-4258-9856)
- Hangwei Fa
Institutions
- Hangzhou Normal University (CN)
- Peking University (CN)
- Ministry of Education (ET)
- First Affiliated Hospital Zhejiang University (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-10-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116400
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00