No abstract

Prostate cancer (PCa) is a leading cause of death among men. The dysregulation of metabolism and autophagy contributes to the progression of PCa. The transcription factor specificity protein 1 (Sp1) is implicated in the regulation of metabolism and autophagy. We confirmed that Sp1 is overexpressed in castration-resistant prostate cancer (CRPC) cells. However, the roles of Sp1 in PCa metabolism and autophagy remain unclear. Thus, in the present study, we retrieved the GSE35988 dataset from Gene Expression Omnibus (GEO) database to reinvestigate Sp1 expression and its role in PCa.We found that in PCa, Sp1 knockdown significantly inhibited cell growth, aerobic glycolysis, and hypoxia-induced autophagy, which were accompanied by an increased G1 cell cycle arrest. Pearson correlation indicated that pyruvate kinase isoenzyme type M2 (PKM2) is positively correlated with Sp1 expression. Western blot analysis demonstrated that Sp1 directly regulates PKM2; therefore, Sp1 modulates metabolism and autophagy in CRPC. Western blot analysis and luciferase reporter assay also indicated that the tumor suppressor miR-361-5p inversely regulates Sp1 by directly targeting the binding site in the 3'UTR of Sp1. miR-361-5p overexpression presented effects that are similar to Sp1 depletion in PCa. In summary, this study is the first to demonstrate that miR-361-5p suppresses the Sp1/PKM2 axis, consequently affecting the progression of PCa and the metabolism and autophagy of PCa cells. Therefore, targeting the miR-361-5p/Sp1/PKM2 pathway has considerable clinical significance in preventing the malignant progression of PCa.

SNAIL is a promising target for the treatment of cancer because it is known to promote epithelial-mesenchymal transition. Recent studies suggest that SNAIL also takes part in metabolic reprogramming and chemotherapy resistance in some cancers. In prostate cancer (PCa), SNAIL has been proved to be required for hypoxia-induced invasion and as a potential marker for predicting the recurrence. However, the role of SNAIL in PCa aberrant metabolism is poorly understood. In this study, we identified that SNAIL regulated cellular growth and energy metabolism through the miR-128-mediated ribosomal protein S6 kinase 1 (RPS6KB1)/HIF-1α/PKM2 signaling pathway which played a key role in the reprogramming of cancer metabolism. Using quantitative RT-PCR (qRT-PCR), we found that SNAIL expression was elevated in castration-resistant prostate cancer tissues compared with androgen-dependent prostate cancer tissues and nontumorous tissues. Depletion of SNAIL increased miR-128 expression levels, inhibited cell growth, reduced glucose consumption and lactate production, and repressed the expression of RPS6KB1, HIF-1α, and PKM2 in PCa cells. Luciferase reporter assays showed the SNAIL regulated miR-128 expression at the transcriptional level and miR-128 modulated RPS6KB1 expression at the translational level. Furthermore, down-expression of miR-128 partially restored the effect of si-SNAIL on the suppression of cellular growth, metabolism, and RPS6KB1/HIF-1α/PKM2 signaling pathway. To our knowledge, it is the first time to demonstrate that SNAIL/miR-128/RPS6KB1 pathway plays a critical role in the progression of PCa.