2. Academic Validation
  3. LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation

LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation

  • Mol Cell. 2023 May 2;S1097-2765(23)00288-5. doi: 10.1016/j.molcel.2023.04.017.
Shelby E Compton 1,  Susan M Kitchen-Goosen 2,  Lisa M DeCamp 2,  Kin H Lau 3,  Batsirai Mabvakure 1,  Matthew Vos 2,  Kelsey S Williams 2,  Kwok-Kin Wong 4,  Xiaobing Shi 5,  Scott B Rothbart 5,  Connie M Krawczyk 2,  Russell G Jones 6
Affiliations

Affiliations

  • 1 Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
  • 2 Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.
  • 3 Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA.
  • 4 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
  • 5 Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
  • 6 Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA. Electronic address: [email protected].
PMID: 37172591 DOI: 10.1016/j.molcel.2023.04.017
Abstract

Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, 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. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.

Keywords

CREB; CREB-regulated transcription coactivator 2; CRTC2; H3K27; IL-1β; IL-6; LIF; LKB1; SIKs; cAMP response element binding protein; histone acetylation; inflammation; interleukin-6; leukemia inhibitory factor; liver kinase B1; salt-inducible kinases.

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