DHX38 restricts chemoresistance by regulating the alternative pre-mRNA splicing of RELL2 in pancreatic ductal adenocarcinoma

Author summaryIntron retention is a form of alternative splicing which has attracted much attention in recent years. More and more studies have shown that intron retention exists widely and affects 80% of the encoded genes, thus regulating gene expression and physiological and pathological processes. Here, we described the role of alternative splicing gene RELL2 and its upstream splicer DHX38 in pancreatic ductal adenocarcinoma. We found that the expression of DHX38 in pancreatic ductal adenocarcinoma was reduced, which led to the retention of the fourth intron of RELL2 and the occurrence of nonsense-mediated mRNA decay, and ultimately inhibit the apoptosis of pancreatic cancer cells, and promote the occurrence of drug resistance in pancreatic cancer. Our work found a new intron retention gene in pancreatic ductal adenocarcinoma, which provide a probable therapeutic target of pancreatic ductal adenocarcinoma. Intron retention plays an important role in cancer progression and chemotherapy resistance and seems to be essential for the maintenance of genome stability in cancer. Here, our goal was to analyze the role of receptor expressed in lymphoid tissue (Relt)-like 2 (RELL2) intron 4 retention in promoting pancreatic ductal adenocarcinoma (PDAC) progression. Our results showed that intron retention (IR) occurs at the fourth intron of RELL2 transcript in gemcitabine resistant PDAC cells, however, the regulatory mechanism and the clinical implications of IR of RELL2 are unclear. Firstly, we found that RELL2 plays an anti-oncogenic role in PDAC by performing in vitro functional assays including cell proliferation, GEM cytotoxicity assay and apoptosis. Subsequently, we identified the upstream gene of RELL2, DEAH-Box Helicase 38 (DHX38), and demonstrated the direct interaction between DHX38 and RELL2 by RIP-qPCR. We also found that altered expression of DHX38 resulted in corresponding changes in intron 4 retention of RELL2. Importantly, we unveiled that overexpression of DHX38 on the basis of knocking down of the fourth intron of RELL2 resulted in an impaired intron 4 intention. Overall, our study identified a new IR site in PDAC, which could be a possible target for PDAC therapy.

Automated summary

The study identified a new intron retention gene in pancreatic ductal adenocarcinoma, which is regulated by the upstream splicer DHX38. The reduction of DHX38 expression leads to the retention of the fourth intron of RELL2, causing nonsense-mediated mRNA decay and inhibiting apoptosis of pancreatic cancer cells, ultimately promoting drug resistance. This research provides a potential therapeutic target for pancreatic ductal adenocarcinoma.