Compton, Shelby Elizabeth;
DeCamp, Lisa M;
Kitchen-Goosen, Susan M;
Lau, Kin;
Dahabieh, Michael S;
Guak, Hannah;
VanderArk, Alexandra;
Vos, Matthew;
Williams, Kelsey S;
Shi, Xiaobing;
Rothbart, Scott B;
Krawczyk, Connie M;
Jones, Russell G
LKB1 controls inflammatory potential through CRTC2-dependent epigenetic remodeling
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Media type:
E-Article
Title:
LKB1 controls inflammatory potential through CRTC2-dependent epigenetic remodeling
Contributor:
Compton, Shelby Elizabeth;
DeCamp, Lisa M;
Kitchen-Goosen, Susan M;
Lau, Kin;
Dahabieh, Michael S;
Guak, Hannah;
VanderArk, Alexandra;
Vos, Matthew;
Williams, Kelsey S;
Shi, Xiaobing;
Rothbart, Scott B;
Krawczyk, Connie M;
Jones, Russell G
imprint:
The American Association of Immunologists, 2023
Description:
<jats:title>Abstract</jats:title>
<jats:p>Deregulated inflammation is a critical feature driving tumor progression in 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.</jats:p>
<jats:p>Supported by the National Institute of General Medical Sciences (NIGMS, R35GM124736), the National Institute of Allergy and Infectious Diseases (NIAID, R21AI153997), the Paul G. Allen Frontiers Group Distinguished Investigator Program, the National Institute of Allergy and Infectious Diseases (NIAID, R01AI165722), and Van Andel Institute.</jats:p>