A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAF^V600E inhibition in melanoma.

ABSTRACT: The BRAF^V600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAF^V600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAF^V600E downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1

SUBMITTER: Zhou J 

PROVIDER: S-EPMC12446969 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature