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.

非调控性炎症是驱动携带肝脏激酶B1（LKB1）突变的肿瘤进展的关键特征，然而，将LKB1突变与非调控性炎症联系起来的机制尚不明确。在本项研究论文中，我们鉴定了由CREB调控的转录共激活因子2（CRTC2）的非调控信号传导作为LKB1缺失后炎症潜力的表观遗传驱动因素。我们证实，LKB1突变使得转化的和非转化的细胞对多种炎症刺激更为敏感，从而促进了细胞因子和趋化因子的过度产生。LKB1缺失触发了下游盐诱导激酶（SIKs）的CRTC2-CREB信号传导的增强，增加了LKB1缺陷细胞中的炎症基因表达。本数据集中包含的免疫印迹数据（用于图4、S2和S3）显示，在鼠源LKB1缺陷MEFs和Kras/LKB1（KPL）突变型肺癌细胞中，CRTC2表现出低磷酸化，而CREB则表现出高磷酸化。