LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation

Deregulated inflammation is a critical feature driving progression of tumors harboring mutations in the Liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. In this research publication we identify deregulated signaling by CREB regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. The immunoblot data contained in this dataset (for Figures 4, S2, and S3) show in murine LKB1-deficient MEFs and Kras/LKB1 (KPL) mutant lung cancer cells that CRTC2 is hypophosphorylated and CREB is hyperphosphorylated.