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.

中文翻译：

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炎症和 DNA 甲基化共同调节 CtBP-PCAF-c-MYC 转录复合物，以激活急性胰腺炎中长链非编码 RNA CASC2 的表达。

长链非编码 RNA (lncRNA) 正在成为参与许多疾病发病机制的重要调节因子。然而，它们是否会导致急性胰腺炎（AP）的发生尚不清楚。在这里，我们确定了一个 lncRNA CASC2（癌症易感性候选 2）在 AP 患者的胰腺组织中显着上调。体外敲除或过表达 CASC2 可以特异性地抑制或诱导两种促炎细胞因子的表达，分别包括 IL6（白细胞介素 6）和 IL17。改变预测与 CASC2 启动子结合的几种转录因子的表达水平，我们发现 c-MYC 可以特异性调节 CASC2 的表达。使用免疫沉淀、质谱和免疫共沉淀分析，我们证明 c-MYC 与 PCAF（p300/CBP 相关因子）和 CtBP1/2（C 端结合蛋白 1 和 2）组装了一个转录复合物，称为 CtBP-PCAF-c-MYC（CPM）复合物。进一步的研究表明，CtBPs 在 AP 患者的胰腺组织中被扩增，它们作为共激活剂起作用以诱导 CASC2 的表达，从而导致 IL6 和 IL17 的上调。此外，我们发现 CtBPs 启动子中 DNA 甲基化水平的降低和炎症刺激共同激活了 CtBPs 的表达。总的来说，我们确定了一个新的信号通路，其中 DNA 甲基化和炎症刺激共同调节 CPM 复合物以激活 CASC2 表达，其诱导进一步激活 IL6 和 IL17 的表达，