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

Patrick J. Cunniff, Nicole Sivetz, Damianos Skopelitis, Olaf Klingbeil, Daniel Toobian, Diogo Maia-Silva, Mikala Egeblad and Christopher R. Vakoc ()
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Patrick J. Cunniff: Cold Spring Harbor Laboratory
Nicole Sivetz: Cold Spring Harbor Laboratory
Damianos Skopelitis: Cold Spring Harbor Laboratory
Olaf Klingbeil: Cold Spring Harbor Laboratory
Daniel Toobian: Cold Spring Harbor Laboratory
Diogo Maia-Silva: Cold Spring Harbor Laboratory
Mikala Egeblad: Johns Hopkins University
Christopher R. Vakoc: Cold Spring Harbor Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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 activity, which have anti-PDAC activity in vivo, suppress KLF5-dependent transcription. These findings define a previously unrecognized mechanism of ATP hydrolysis-dependent transcriptional coactivation and highlight a potential therapeutic strategy for modulating aberrant lineage programs in cancer.

Date: 2025
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DOI: 10.1038/s41467-025-66007-0

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