Human HDAC6 senses valine abundancy to regulate DNA damage

Jiali Jin, Tong Meng, Yuanyuan Yu, Shuheng Wu, Chen-Chen Jiao, Sihui Song, Ya-Xu Li, Yu Zhang, Yuan-Yuan Zhao, Xinran Li, Zixin Wang, Yu-Fan Liu, Runzhi Huang, Jieling Qin, Yihua Chen, Hao Cao, Xiao Tan, Xin Ge, Cong Jiang, Jianhuang Xue, Jian Yuan, Dianqing Wu, Wei Wu, Ci-Zhong Jiang and Ping Wang ()
Additional contact information
Jiali Jin: Tongji University
Tong Meng: Tongji University
Yuanyuan Yu: Tongji University
Shuheng Wu: Chinese Academy of Sciences
Chen-Chen Jiao: Tongji University
Sihui Song: Tongji University
Ya-Xu Li: Tongji University
Yu Zhang: Tongji University
Yuan-Yuan Zhao: Tongji University
Xinran Li: Tongji University
Zixin Wang: Tongji University
Yu-Fan Liu: Tongji University
Runzhi Huang: Tongji University
Jieling Qin: Tongji University
Yihua Chen: East China Normal University
Hao Cao: Shenyang Pharmaceutical University
Xiao Tan: Tongji University
Xin Ge: Tongji University
Cong Jiang: Tongji University
Jianhuang Xue: Tongji University
Jian Yuan: Tongji University School of Medicine
Dianqing Wu: Yale School of Medicine
Wei Wu: Chinese Academy of Sciences
Ci-Zhong Jiang: Tongji University
Ping Wang: Tongji University

Nature, 2025, vol. 637, issue 8044, 215-223

Abstract: Abstract As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression1–3. However, the mechanism by which cellular valine abundancy is sensed for subsequent cellular functions remains undefined. Here we identify that human histone deacetylase 6 (HDAC6) serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. The nucleus and cytoplasm shuttling of human, but not mouse, HDAC6 is tightly controlled by the intracellular levels of valine. Valine deprivation leads to HDAC6 retention in the nucleus and induces DNA damage. Mechanistically, nuclear-localized HDAC6 binds and deacetylates ten-eleven translocation 2 (TET2) to initiate active DNA demethylation, which promotes DNA damage through thymine DNA glycosylase-driven excision. Dietary valine restriction inhibits tumour growth in xenograft and patient-derived xenograft models, and enhances the therapeutic efficacy of PARP inhibitors. Collectively, our study identifies human HDAC6 as a valine sensor that mediates active DNA demethylation and DNA damage in response to valine deprivation, and highlights the potential of dietary valine restriction for cancer treatment.

Date: 2025
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DOI: 10.1038/s41586-024-08248-5

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