The Lysine Demethylase Kdm4C is an Oncogenic Driver and Regulates ERK Activity in KRAS Mutant Pancreatic Ductal Adenocarcinoma [RNA-Seq]

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 to non-neoplastic 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 proteomics analyses revealed that loss of Kdm4C in both human and murine PDAC cell lines was associated with 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 via compensatory upregulation of other KDM4 family members. To bypass this genetic compensation, we tested a preclinical pan-KDM4 inhibitor TACH107 and confirmed its efficacy in in vitro and in vivo PDAC models including those resistant to the covalent KRASG12D inhibitor MTRX1133. 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.