DPF2 reads histone lactylation to drive transcription and tumorigenesis

• 成果类型: Article
• 署名作者: Zhai, Guijin; Niu, Ziping; Jiang, Zixin; Zhao, Fei; Wang, Siyu; Chen, Chen; Zheng, Wei; Wang, Aiyuan; Zang, Yong; Han, Yanpu; Zhang, Kai
• 署名单位: Tianjin Medical University; Shandong Laboratory of Yantai Drug Discovery; Tianjin Medical University; Tianjin Medical University; Tianjin Medical University; Tianjin Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14123
• DOI: 10.1073/pnas.2421496121
• 发表日期: 2024-12-10
• 关键词: chemical proteomics reveals; metabolic-regulation; gene-expression; crotonylation; RECOGNITION; acetylation; dna

摘要

Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. However, how this histone mark acts in cancers remains unexplored due in part to a lack of knowledge about its reader proteins. Here, we observe that cervical cancer (CC) cells undergo metabolic reprogram by which lactate accumulation and thereby boosts histone lactylation, particularly H3K14la. Utilizing a multivalent photoaffinity probe in combination with quantitative proteomics approach, we identify DPF2 as a candidate target of H3K14la. Biochemical studies as well as CUT&Tag analysis reveal that DPF2 is capable of binding to H3K14la and colocalizes with it on promoters of oncogenic genes. Notably, disrupting the DPF2-H3K14la interaction through structure- guided mutation blunts those cancer- related gene expression along with cell survival. Together, our findings reveal DPF2 as a bona fide H3K14la effector that couples histone lactylation to gene transcription and cell survival, offering insight into how histone Kla engages in transcription and tumorigenesis.