KLF5 activates lncRNA DANCR and inhibits cancer cell autophagy accelerating gastric cancer progression

Abstract

Cancer cell autophagy has been associated with the progression of gastric cancer (GC), but involvement of long noncoding RNAs (lncRNAs) remains unclear. Initial bioinformatics analysis has identified abnormally highly expressed KLF5 in GC, as well as the predicted regulatory mechanism associating with lncRNA DANCR, miR-194, and AKT2. The expression of KLF5, DANCR, and AKT2 in GC tissue was upregulated, and the expression of miR-194 was downregulated. We knocked KLF5 down and manipulated the expression of DANCR, miR-194, and AKT2 to characterize their roles in GC cell viability, autophagy, and apoptosis. The mechanistic investigations revealed that KLF5 activated the transcription of DANCR in the promoter region and elevated its expression. DANCR acted as a miR-194 sponge to repress its expression in GC. MiR-194 targeted and inhibited AKT2 expression. Silencing KLF5 augmented GC cell autophagy, apoptosis and impeded its viability through the DANCR/miR-194/AKT2 axis. The tumor-inhibiting properties of KLF5 knockdown were substantiated in vivo. Together, our study uncovered the oncogenic role of KLF5-dependent lncRNA DANCR transcription in GC in vivo and in vitro, which implicates the miR-194/AKT2 axis in tumor growth regulation, and it may be a potential therapeutic target for human GC.

Autophagy Related Noncoding RNAs: Emerging Regulatory Factors of Gastric Cancer

“… 8 Wang et al found that lncMALAT1 can promote IL-6 secretion by blocking autophagy flux in GC cells, causing the activation of normal to cancer-related fibroblast transformation, which plays an important role in the development of GC. 45 In a similar study, Chen et al reported that the expressions of KLF5 and lncDANCR were up-regulated in GC tissues, 18 where KLF5 activated lncDANCR, inhibited autophagy of GC cells, and accelerated the progression of GC. 18 Other autophagy-related lncRNAs play important roles in the occurrence, development, and treatment of GC.…”

“…8 The researchers found that LncSNHG11 aggravated oncogenic autophagy to facilitate the stemness, proliferation, migration, invasion, and EMT in GC by activating the Wnt/β-catenin pathway. 8 Wang et al found that lncMALAT1 can promote IL-6 secretion by blocking autophagy flux in GC 45 In a similar study, Chen et al reported that the expressions of KLF5 and lncDANCR were up-regulated in GC tissues, 18 where KLF5 activated lncDANCR, inhibited autophagy of GC cells, and accelerated the progression of GC. 18 Other autophagy-related lncRNAs play important roles in the occurrence, development, and treatment of GC.…”

“…8 Wang et al found that lncMALAT1 can promote IL-6 secretion by blocking autophagy flux in GC 45 In a similar study, Chen et al reported that the expressions of KLF5 and lncDANCR were up-regulated in GC tissues, 18 where KLF5 activated lncDANCR, inhibited autophagy of GC cells, and accelerated the progression of GC. 18 Other autophagy-related lncRNAs play important roles in the occurrence, development, and treatment of GC. [46][47][48][49][50] These studies provide new insights into the early diagnosis and clinical treatment of GC.…”

“…KLF5 activated lncRNA DANCR and inhibited GC cell autophagy and apoptosis through the miR-194/AKT2 axis, thereby accelerating the progression of GC. 18 Autophagy imbalance is significantly associated with drug resistance in many cancers including GC. It is reported that the CAGE/miR-181b-5p/S1PR1 axis promoted drug resistance of GC cells by mediating autophagy.…”

A review on the role of DANCR in the carcinogenesis

“…Another study in gastric cancer cells has shown that KLF5 activates DANCR transcription. DANCR could act as a molecular sponge for miR-194 to suppress its expression and increase expression of AKT2, thus promoting gastric carcinogenesis through inhibition of autophagy [ 31 ]. Moreover, expression of DANCR in gastric cancer can be induced by SALL4 [ 32 ].…”