SIRT1 enhances matrix metalloproteinase‐2 expression and tumor cell invasion in prostate cancer cells

Abstract

BACKGROUND: Matrix metalloproteinase-2 (MMP2) has been shown to play an important role in cancer cell invasion and the expression of MMP2 is associated with the poor prognosis of prostate cancer; however, the mechanism of MMP2 expression is largely unknown. SIRT1 is a nicotinamide adenine dinucleotide-dependent histone deacetylase (class III HDAC) that has recently been shown to have implications in regulating cancer cell growth and apoptosis. The purpose of this study is to determine the role of SIRT1 in regulating MMP2 expression and tumor invasion in prostate cancer cells. METHODS: The interfering RNAi was used to knockdown SIRT1 from prostate cancer cells. Immunoblots, RT-PCR, zymographic assays, co-immunoprecipitation, analysis and transwell assays were used to examine the effects of SIRT1 silencing on MMP2 expression and activity, on SIRT1 and MMP2 interaction, and on prostate cancer cell invasion. The immuno-histochemical assay was performed to study SIRT1 expression in prostate cancer tissues. RESULTS: We show that SIRT1 associates and deacetylates MMP2 and SIRT1 regulates MMP2 expression by controlling MMP2 protein stability through the proteosomal pathway. Thus, we demonstrated a novel mechanism in that MMP2 expression can be regulated at the posttranslational level by SIRT1. Furthermore, we determined that SIRT1 inhibition reduced prostate cancer cell invasion and SIRT1 is highly expressed in advanced prostate cancer tissues. CONCLUSIONS: SIRT1 is an important regulator of MMP2 expression, activity, and prostate cancer cell invasion. Overexpressed SIRT1 in advanced prostate cancer may play an important role in prostate cancer progression.