BioProject

Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. More...

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 boost 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 co-localizes with it on promoters of oncogenic genes. Notably, disrupting the association between DPF2 and histone lactylation 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. Overall design: On the basis of our findings that the correlation between DPF2 and H3K14la at promoter regions and lactate boosts H3K14la instead of H3K14ac, we propose that DPF2-H3K14la recognition confer transcription, and the genes modulated by this recognition could be obtained through a quantitative RNA-Seq analysis of cells expressing WT-DPF2 and Mut-DPF2 prior to lactate supplementation. To assess this, we performed RNA-Seq detection from WT-DPF2 or Mut-DPF2 expressed cells upon lactate pre-treatment. Less...