LncRNA HIF1A-AS1 promotes gemcitabine resistance of pancreatic cancer by enhancing glycolysis through modulating the AKT/YB1/HIF-1α pathway.

Gemcitabine (GEM) resistance is a major challenge for chemotherapy of pancreatic cancer (PC). Previous studies have reported on the role of lncRNA in tumorigenesis of PC, however, the involvement of lncRNA in the development of GEM resistance of PC remains unclear. In the present study, we demonstrated that the antisense RNA1 of HIF-1α (HIF1A-AS1) was significantly elevated in the GEM-resistant PC cells. Gain- and lost-of-function experiments validated that HIF1A-AS1 promoted GEM resistance of PC cells both in vitro and vivo. We further revealed that HIF1A-AS1 upregulated HIF-1α expression and thus promoted glycolysis to enhance GEM resistance of PC cells. Mechanistically, HIF1A-AS1 facilitated the interaction between serine/threonine kinase AKT and Y-box binding protein 1 (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIF-1α mRNA which consequently promoted translation of HIF-1α. Furthermore, HIF-1α promoted HIF1A-AS1 transcription by directly binding to the HIF-1α response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF-1α were upregulated in PC tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF-1α which contributes to GEM resistance of PC and indicate that HIF1A-AS1 might serve as a novel therapeutic target for GEM resistance of PC.