Targeting MTA1/HIF-1a signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

Authors: BUTT, NASIR - University Of Mississippi; KUMAR, AVINASH - University Of Mississippi; DHAR, SWATI - University Of Mississippi; Rimando, Agnes; AKHTAR, ISRAH - University Of Mississippi; HANCOCK, JON - University Of Mississippi; LAGE, JANICE - University Of Mississippi; POUND, CHARLES - University Of Mississippi; LEWIN, JACK - University Of Mississippi; GOMEZ, CHRISTIAN - University Of Mississippi; LEVENSON, ANAIT - University Of Mississippi

Submitted to: Cancer Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2017
Publication Date: 10/11/2017
Citation: Butt, N.A., Kumar, A., Dhar, S., Rimando, A.M., Akhtar, I., Hancock, J.C., Lage, J.M., Pound, C.R., Lewin, J.R., Gomez, C.R., Levenson, A.S. 2017. Targeting MTA1/HIF-1a signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression. Cancer Medicine. 6(11):2673-2685.
DOI: https://doi.org/10.1002/cam4.1209

Interpretive Summary: The dimeric protein unit consisting of metastasis associated protein 1 (MTA1) and histone deacetylase (HDAC) is a prostate cancer progression regulator, which is overexpressed in metastatic prostate cancer. In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific mouse model as well as anti-tumorigenic effects of stilbenes. In the current study, we examined in mice whether the MTA1/HDAC unit would be inhibited by using combination of pterostilbene (Pter) and a clinically approved HDAC inhibitor, SAHA. The combination of Pter and SAHA was effective in inhibiting tumor growth in these mice. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in additional decline of tumor progression. We also performed in vitro studies using prostate cancer (PCa) cell lines, and treated the cells with a combination of Pter and SAHA. We found that treatment of PCa cells with Pter and low dose SAHA resulted in more potent inhibition of MTA1 compared to a high dose SAHA alone. Our study provides pre-clinical evidence that combination treatment with Pter and SAHA inhibits tumor-promoting signaling in prostate cancer. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in prostate cancer.

Technical Abstract: The metastasis-associated protein 1(MTA1)/ histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer. In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model as well as anti-tumorigenic effects of stilbenes through inhibition of MTA1-associated signaling including deacetylation of tumor suppressors. In the current study, we examined whether inhibition of MTA1/HDAC using combination of pterostilbene (Pter) and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamine, vorinostat) which also downregulates MTA1 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; Rosa26Luc/+) to evaluate the anti-cancer efficacy of Pter/SAHA combinatorial approach. The combination of Pter and SAHA was effective in inhibiting tumor growth in these mice. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated pro-angiogenic factors HIF-1a, VEGF, and IL-1ß leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/ HIF-1a than by high dose SAHA alone. Our study provides pre-clinical evidence that Pter and SAHA combination treatment inhibits MTA1/HIF-1a tumor-promoting signaling in prostate cancer. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in prostate cancer.