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Metformin inhibits SUV39H1-mediated migration of prostate cancer cells.

ABSTRACT: Prostate cancer (PCa) is a leading cause of cancer-related death among men, largely due to incurable distant metastases. Metformin, the most common used anti-type-2 diabetes medicine, has been linked to reduced cancer risk and better diagnosis. We found that metformin was able to inhibit PCa cell migration, which correlates with tumor metastatic capability. The pathogenesis and progression of tumors are closely related to dysregulated gene expression in tumor cells through epigenetic alterations such as DNA methylation and histone modifications. We found that the level of SUV39H1, a histone methyltransferase of H3 Lys9, was reduced in metformin-treated PCa cells in a time-dependent manner. SUV39H1 overexpression increased PCa migration, whereas SUV39H1 depletion suppressed PCa cell migration. There is a positive correlation between SUV39H1 expression and PCa pathological stages. We further showed that both metformin treatment and SUV39H1 knockout in PCa cells can reduce integrin ?V and ?1 proteins, as well as their downstream phosphorylated focal adhesion kinase (FAK) levels, which is essential for functional adhesion signaling and tumor cell migration. Taken together, metformin reduced SUV39H1 to inhibit migration of PCa cells via disturbing the integrin-FAK signaling. Our study suggests SUV39H1 as a novel target to inhibit PCa cell migration.

SUBMITTER: Yu T

PROVIDER: S-EPMC5523061 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Metformin inhibits SUV39H1-mediated migration of prostate cancer cells.

Yu T T Wang C C Yang J J Guo Y Y Wu Y Y Li X X

Oncogenesis 20170501 5

Prostate cancer (PCa) is a leading cause of cancer-related death among men, largely due to incurable distant metastases. Metformin, the most common used anti-type-2 diabetes medicine, has been linked to reduced cancer risk and better diagnosis. We found that metformin was able to inhibit PCa cell migration, which correlates with tumor metastatic capability. The pathogenesis and progression of tumors are closely related to dysregulated gene expression in tumor cells through epigenetic alterations ...[more]

PMID: 28459432

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Project description:BackgroundG protein-coupled bile acid receptor 1 (GPBAR1) is a G protein-coupled receptor for bile acids, which is widely expressed in many human tissues. Patchouli alcohol (PA) has been shown to have an anti-cancer effect, including in prostate cancer (PCa). This study sought to confirm the regulatory mechanism of GPBAR1 in the anti-cancer activity of PA in PCa.MethodsThe SwissTargetPrediction website (Pro >0) was used to predict the target of PA. The UALCAN and The Cancer Genome Atlas-Prostate cohort was used to examine the differentially expressed genes and PCa recurrence. A gene set enrichment analysis (GSEA) was conducted to analyze the relationship between the expression of GPBAR1 and PCa proliferation, migration, and invasion. Cell proliferation, migration, and invasion were assessed by colony formation, 5-Ethynyl-2'-deoxyuridine staining, cell scratch assays, and Transwell invasion assays, respectively. A xenograft animal model was established to assess the effect of PA on tumor growth in vivo. GPBAR1 protein and apoptosis related protein expression was measured by western blot.ResultsGPBAR1 was a PA target predicted by the SwissTargetPrediction website. PA inhibited the expression of GPBAR1 in PCa cells in a time- and dose-dependent manner. The abnormal expression of GPBAR1 was related to cell proliferation, migration, and invasion. Additionally, GPBAR1 overexpression promoted the cell proliferation, migration, and invasion, and inhibited the apoptosis of PCa cells. GPBAR1 silencing inhibited the cell proliferation, migration, and invasion, and promoted the apoptosis of PCa cells. High expressions of GPBAR1 suppressed tumor growth in tumor-bearing mice. Further, GPBAR1 promoted the activation of nuclear factor kappa B (NF-κB) signaling, and PA regulated the malignant phenotypes of PCa cells via the NF-κB signaling pathway mediated by GPBAR1.ConclusionsGPBAR1 is a promising drug target of PA, and was shown to regulate the proliferation, apoptosis, migration, and invasion of PCa cells through GPBAR1/NF-κB inhibition.

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Metformin inhibits SUV39H1-mediated migration of prostate cancer cells.

Publications

Metformin inhibits SUV39H1-mediated migration of prostate cancer cells.

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