DPF2 reads histone lactylation to drive transcription and tumorigenesis

作者：Guijin Zhai, Ziping Niu, Zixin Jiang, Fei Zhao, Siyu Wang, Chen Chen, Wei Zheng, Aiyuan Wang, Yong Zang, Yanpu Han, Kai Zhang · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2421496121 · 被引用次数：120 · 研究领域：Epigenetics and DNA Methylation、Genomics and Chromatin Dynamics、RNA modifications and cancer

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.