KDM5A Modulates KRAS-Associated Transcriptional Programs in Pancreatic Cancer

Jasper Chen (Advisors: Albert Koong, MD, PhD; and Ronald DePinho, MD; Cullen Taniguchi, MD, PhD (†)  

             Aberrant chromatin regulation is a defining feature of pancreatic ductal adenocarcinoma (PDAC), but the mechanisms linking oncogenic KRAS to downstream epigenetic states remain incompletely understood. In this study, we investigated the H3K4 demethylase KDM5A as a chromatin regulator downstream of KRAS in an inducible mouse model of PDAC. Using doxycycline withdrawal and pharmacologic KRAS inhibition, we found that active KRAS signaling is associated with reduced KDM5A protein abundance, consistent with predominantly post-translational regulation. Because KDM5A counteracts the active H3K4me3 mark and has known links to cell-cycle control, we examined whether it contributes to KRAS-associated transcriptional programs.

             Chromatin profiling and transcriptomic analysis showed that KDM5A localizes mainly to promoter-proximal regions and is associated with genes involved in proliferative and metabolic pathways, including MYC, E2F, oxidative phosphorylation, and mTOR signaling. Perturbation of KDM5A shifted these pathways, supporting a role for KDM5A promoter occupancy in regulating these programs. Proximity labeling placed KDM5A within regulatory neighborhoods containing both activating and repressive chromatin machinery. Finally, loss of KDM5A accelerated tumor growth in an orthotopic mouse model. Together, these results support a model in which reduced KDM5A contributes to the transcriptional state associated with KRAS-driven pancreatic tumorigenesis.

Advisory Committee:

• Albert Koong, MD, PhD, Chair
• Ronald DePinho, MD, Co-Chair
• Cullen Taniguchi, MD, PhD, Co-Chair (†)
• Traver Hart, PhD
• Antonio Marzio, PhD
• Dianna Milewicz, MD, PhD
• Kunal Rai, PhD
• Gregg Semenza, MD, PhD