Int J Biol Sci 2020; 16(12):2116-2130. doi:10.7150/ijbs.43557

Research Paper

Inflammation and DNA methylation coregulate the CtBP-PCAF-c-MYC transcriptional complex to activate the expression of a long non-coding RNA CASC2 in acute pancreatitis

Jun Zeng1, Jian-Yong Chen1, Jun Meng1, Zhi Chen2,3✉

1. Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China
2. Department of critical care medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China
3. Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.

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Citation:
Zeng J, Chen JY, Meng J, Chen Z. Inflammation and DNA methylation coregulate the CtBP-PCAF-c-MYC transcriptional complex to activate the expression of a long non-coding RNA CASC2 in acute pancreatitis. Int J Biol Sci 2020; 16(12):2116-2130. doi:10.7150/ijbs.43557. Available from http://www.ijbs.com/v16p2116.htm

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Abstract

Long non-coding RNAs (lncRNAs) are emerging as important regulators involved in the pathogenesis of many diseases. However, it is still unknown if they contribute to the occurrence of acute pancreatitis (AP). Here, we identified a lncRNA CASC2 (Cancer Susceptibility Candidate 2) was significantly upregulated in the pancreatic tissues from AP patients. Knockdown or overexpression of CASC2 in vitro could specifically repress or induce the expression of two proinflammatory cytokines including IL6 (Interleukin 6) and IL17, respectively. Changing the expression levels of several transcription factors that were predicted to bind to the promoter of CASC2, we found c-MYC could specifically regulate the expression of CASC2. Using immunoprecipitation, mass spectrometry, and co-immunoprecipitation assays, we proved that c-MYC assembled a transcriptional complex with PCAF (p300/CBP-associated Factor) and CtBP1/2 (C-terminal Binding Protein 1 and 2), terming as the CtBP-PCAF-c-MYC (CPM) complex. Further investigation revealed that CtBPs were amplified in the pancreatic tissues from AP patients and they functioned as coactivators to induce the expression of CASC2 and thus led to the upregulation of IL6 and IL17. Moreover, we identified that decreased DNA methylation levels in the promoters of CtBPs and inflammatory stimuli coactivated the expression of CtBPs. Collectively, we identified a new signaling pathway in which DNA methylation and inflammatory stimuli coregulate the CPM complex to activate CASC2 expression, whose induction further activates the expression of IL6 and IL17, eventually aggravating inflammation response and causing the pathology of AP.

Keywords: acute pancreatitis, CASC2, CtBP, PCAF, c-MYC