DPF2 reads histone lactylation to drive transcription and tumorigenesis [RNA-seq]

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. 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.