The Lysine Demethylase KDM4C Is an Oncogenic Driver and Regulates ERK Activity in KRAS-Mutant Pancreatic Ductal Adenocarcinoma

Authors

Menna-T-Allah Shaheen
Sarah Dhebat
Kimal I Rajapakshe
Bidyut Ghosh
Benson Chellakkan Selvanesan
Shariq S Ansari
Cara L Haymaker
Dorsay Sadeghian
Huamin Wang
Ching-Fei Li
Haoqiang Ying
Anirban Maitra

Language

English

Publication Date

1-1-2026

Journal

Cancer Research Communications

DOI

10.1158/2767-9764.CRC-25-0278

PMID

41490602

PMCID

PMC12856980

PubMedCentral® Posted Date

1-30-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Deregulation of proteins involved in chromatin regulation is common in pancreatic ductal adenocarcinoma (PDAC). Lysine demethylase 4C (KDM4C) is one of the chromatin-modifying proteins frequently overexpressed across multiple solid cancers and is linked to chromatin instability, increased cell proliferation, and enhanced stem cell–like behavior. We observed upregulation of KDM4C protein in a panel of human PDAC cell lines and patient samples compared with nonneoplastic controls. CRISPR/Cas9-mediated deletion of KDM4C in human and murine PDAC cells reduced proliferation, clonogenicity, and increased survival of orthotopically implanted murine PDAC allografts. Transcriptomic and proteomic analyses revealed that loss of KDM4C in both human and murine PDAC cell lines was associated with the reduction of activated phospho-ERK, a pivotal effector downstream of mutant RAS. Using proximity labeling, we identified the histone deacetylase SIRT1 as a novel interacting protein with KDM4C via the latter’s Tudor reader domain. SIRT1-mediated deacetylation leads to repression of downstream targets, including the dual specificity phosphatase DUSP2, which is known to inactivate ERK via dephosphorylation. In vitro propagation of KDM4C-null PDAC lines eventually led to adaptation and restitution of ERK signaling, with rescue of the KDM4C loss induced growth suppression. To bypass this adaptive phenomenon, we tested a preclinical pan-KDM4 inhibitor TACH107 and confirmed its efficacy in in vitro and in vivo PDAC models. Our studies identify KDM4C as an oncogenic molecule that sustains ERK signaling in KRAS-mutant PDAC and can be broadly targeted via small-molecule inhibitors.

Significance:

Our data suggests that KDM4C is a novel regulator of ERK signaling, the main effector pathway downstream of mutant RAS. This is the first demonstration linking the requirement of sustained KDM4 activity to ERK signaling in cancer and presents an opportunity to leverage this oncogenic pathway for therapeutic intervention.

Keywords

Carcinoma, Pancreatic Ductal, Humans, Animals, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Mice, Jumonji Domain-Containing Histone Demethylases, Cell Line, Tumor, Mutation, Cell Proliferation, Gene Expression Regulation, Neoplastic, MAP Kinase Signaling System

Published Open-Access

yes

Recommended Citation

Shaheen, Menna-T-Allah; Dhebat, Sarah; Rajapakshe, Kimal I; et al., "The Lysine Demethylase KDM4C Is an Oncogenic Driver and Regulates ERK Activity in KRAS-Mutant Pancreatic Ductal Adenocarcinoma" (2026). Faculty, Staff and Student Publications. 5813.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5813