KLF5 enables dichotomous lineage programs in pancreatic cancer via the AAA+ ATPase coactivators RUVBL1 and RUVBL2.

ABSTRACT: Lineage plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor heterogeneity and therapeutic resistance. Here, we identify KLF5 as a dynamic master regulator of epithelial lineage identity in PDAC, with dichotomous roles in promoting either classical or basal-like transcriptional programs. Through unbiased proteomic and genetic screens, we uncover the AAA+ ATPases RUVBL1 and RUVBL2 as essential coactivators of KLF5 across both lineage states. We demonstrate that ATP hydrolysis by RUVBL1/2 is required for the stable interaction with an intrinsically disordered region of KLF5, enabling its recruitment to lineage-specific enhancers and driving transcriptional regulation of identity-defining genes. Notably, small-molecule inhibitors of RUVBL1/2 ATPase acti

SUBMITTER: Cunniff PJ 

PROVIDER: S-EPMC12619835 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature