Targeting <scp>MTA</scp>1/<scp>HIF</scp>‐1<i>α</i> signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

Abstract

Abstract The metastasis‐associated protein 1( MTA 1)/histone deacetylase ( HDAC ) unit is a cancer progression‐related epigenetic regulator, which is overexpressed in hormone‐refractory and metastatic prostate cancer ( PC a). In our previous studies, we found a significantly increased MTA 1 expression in a prostate‐specific Pten ‐null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA 1/ HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN . In this study, we examined whether inhibition of MTA 1/ HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA 1, could block prostate tumor progression in vivo . We generated and utilized a luciferase reporter in a prostate‐specific Pten ‐null mouse model ( Pb‐Cre + ; Pten f/f ; Rosa26 Luc /+ ) to evaluate the anticancer efficacy of Pter/ SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA 1‐associated proangiogenic factors HIF ‐1 α , VEGF , and IL ‐1 β leading to decreased angiogenesis. In addition, treatment of PC a cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA 1/ HIF ‐1 α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/ SAHA combination treatment inhibits MTA 1/ HIF ‐1 α tumor‐promoting signaling in PC a. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA 1‐targeted therapies in PC a.