LKB1 controls inflammatory potential through CRTC2-dependent epigenetic remodeling

Abstract Deregulated inflammation is a critical feature driving tumor progression in tumors harboring mutations the Liver kinase B1 (LKB1), yet mechanisms linking LKB1 to deregulated remain undefined. Here, we identify signaling by CREB regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream loss. We demonstrate that sensitize both transformed and non-transformed cells diverse stimuli, promoting heightened cytokine chemokine production. loss triggers elevated CRTC2-CREB salt inducible kinases (SIKs), increasing gene expression LKB1-deficient cells. Mechanistically, CRTC2 cooperates with histone acetyltransferases CBP/p300 deposit acetylation marks associated active (i.e., H3K27ac) at loci, expression. Together, our data reveal previously undefined anti-inflammatory program, reinforced through CRTC2-dependent modification signaling, links metabolic states cell-intrinsic potential. Supported National Institute General Medical Sciences (NIGMS, R35GM124736), Allergy Infectious Diseases (NIAID, R21AI153997), Paul G. Allen Frontiers Group Distinguished Investigator Program, R01AI165722), Van Andel Institute.