SIRT3 inhibits prostate cancer metastasis through regulation of FOXO3A by suppressing Wnt/β-catenin pathway

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Abstract

SIRT3, a mitochondrial NAD+-dependent deacetylase, has been reported to restrain prostate cancer growth both in vitro and in vivo, however, its role in metastatic prostate cancer has not been revealed. In this study, we reported that SIRT3 inhibited the epithelial-mesenchymal transition (EMT) and migration of prostatic cancer cells in vitro and their metastasis in vivo. Consistently, based on analyses of tissue microarray and microarray datasets, lower SIRT3 expression level was correlated with higher prostate cancer Gleason scores, and SIRT3 expression were significantly decreased in metastatic tissues compared with prostate tumor tissues. Mechanistically, SIRT3 promoted FOXO3A expression by attenuating Wnt/β-catenin pathway, thereby inhibiting EMT and migration of prostate cancer cells. Indeed, SIRT3's inhibitory effect on EMT and migration of prostate cancer cells can be rescued after applying Wnt/β-catenin pathway activator LiCl, or boosted by wnt inhibitor XAV939. Together, this study revealed a novel mechanism for prostate cancer metastasis that involves SIRT3/ Wnt/β-catenin/ FOXO3A signaling to modulate EMT and cell migration.

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