Glucose dysregulation promotes oncogenesis in human bladder cancer by regulating autophagy and YAP1/TAZ expression

Abstract

Glucose dysregulation is strongly correlated with cancer development, and cancer is prevalent in patients with Type 2 diabetes (T2D). We aimed to elucidate the mechanism underlying autophagy in response to glucose dysregulation in human bladder cancer (BC). 220 BC patients were included in this retrospective study. The expression of YAP1, TAZ and AMPK, EMT‐associated markers, and autophagy marker proteins was analysed by immunohistochemistry, western blotting, and quantitative real‐time PCR (qPCR). Further, T24 and UMUC‐3 BC cells were cultured in media with different glucose concentrations, and the expression of YAP1, TAZ, AMPK and EMT‐associated markers, and autophagy marker proteins was analysed by western blotting and qPCR. Autophagy was observed by immunofluorescence and electron microscopy. BC cell viability was tested using MTT assays. A xenograft nude mouse model of diabetes was used to evaluate tumour growth, metastasis and survival. A poorer pathologic grade and tumour‐node‐metastasis stage were observed in patients with BC with comorbid T2D than in others with BC. YAP1 and TAZ were upregulated in BC samples from patients with T2D. Mechanistically, high glucose (HG) promoted BC progression both in vitro and in vivo and inhibited autophagy. Specifically, various autophagy marker proteins and AMPK were negatively regulated under HG conditions and correlated with YAP1 and TAZ expression. These results demonstrate that HG inhibits autophagy and promotes cancer development in BC. YAP1/TAZ/AMPK signalling plays a crucial role in regulating glucose dysregulation during autophagy. Targeting these effectors exhibits therapeutic significance and can serve as prognostic markers in BC patients with T2D.

circELP2 reverse‐splicing biogenesis and function as a pro‐fibrogenic factor by targeting mitochondrial quality control pathway

“…31,32 Therefore, YAP1/TAZ has been a promising target for preventing abnormal remodelling in numerous diseases. [33][34][35] Guérin A et al once have reported that limb expression 1 (LIX1) downregulation alters mitochondrial quality control pathway to control the fate of digestive mesenchyme-derived cells by regulating YAP1 and TAZ activity. 36 Here, we presented that YAP1 and TAZ can bind to mTORC1 to activate or inhibit the target genes in mitochondrial quality control pathway.…”