YEATS4 reads histone crotonylation to promote fatty acid metabolism and cancer cell stemness

Zijun Peng; Huajing Yu; Yizhou Wang; Dan Zhao; Hangwei Fa; Leyi Qin; Yilei Ma; Mengyang Geng; Yuqing Wu; Ge Wu; Xin Wu; Chengying Zhang; Yue Wang; Jianying Liu; Haitao Li; Zhimin Lu; Yongfeng Shang; Jing Liang

doi:10.1016/j.celrep.2025.116400

YEATS4 reads histone crotonylation to promote fatty acid metabolism and cancer cell stemness

Cell Rep. 2025 Oct 28;44(10):116400. doi: 10.1016/j.celrep.2025.116400. Epub 2025 Oct 7.

Authors

Zijun Peng¹, Huajing Yu¹, Yizhou Wang¹, Dan Zhao², Hangwei Fa¹, Leyi Qin¹, Yilei Ma¹, Mengyang Geng¹, Yuqing Wu¹, Ge Wu¹, Xin Wu¹, Chengying Zhang¹, Yue Wang³, Jianying Liu⁴, Haitao Li⁵, Zhimin Lu⁶, Yongfeng Shang⁷, Jing Liang⁸

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
² Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
³ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
⁴ Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
⁵ State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
⁶ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China.
⁷ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China. Electronic address: yshang@hsc.pku.edu.cn.
⁸ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: liang_jing@hsc.pku.edu.cn.

PMID: 41060805
DOI: 10.1016/j.celrep.2025.116400

Abstract

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⁺ breast cancer stem cells, and is correlated with poor prognosis of breast cancer patients, especially the ER⁺ 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.

Keywords: CP: Cancer; CP: Molecular biology; YEATS4; breast cancer stemness; fatty acid metabolism; histone crotonylation.

MeSH terms

Animals
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Cell Proliferation
Fatty Acids* / metabolism
Female
Gene Expression Regulation, Neoplastic
Histones* / metabolism
Humans
Lipid Metabolism
Lysine / metabolism
Mice
Neoplastic Stem Cells* / metabolism
Neoplastic Stem Cells* / pathology

Substances

Histones
Fatty Acids
Lysine