Introduction. Sirtuin family consists of NAD+-dependent class III histone deacetylases (HDACs). Sirtuin family members (SIRT1-SIRT7) were shown to regulate a variety of physiopathological process, including aging, cellular proliferation, metabolism, and autophagy. Prior studies report SIRT1 as either an oncogene or a tumor suppressor depending upon the cell type and system. However, a reduced expression of SIRT1 in prostate cancer has been reported, supporting the view of SIRT1 as a tumor suppressor. Deregulated intracellular reactive oxygen species (ROS) production induces oxidative stress and damage of nucleic acids, proteins and lipids and may contribute to tumorigenesis. Herein, we provide in vivo support for SIRT1 as a tumor suppressor in prostate cancer. The mechanism appears to involve SIRT1-mediated inhibition of A) mitochondrial ROS production and B) mitophagy.

Materials and methods. 7 month old Sirt1 transgenic mice were used. To investigate the molecular mechanisms through which SIRT1 regulate mitochondrial ROS production and mitophagy process, 3T3 cells wild type (Sirt1+/+) and SIRT1 knockout (Sirt1-/-) were used.

Results. Our clinical and experimental data show a decrease in both SIRT1 expression associated with reduced patient survival probability. A histological evaluation of the H&E performed on both Sirt1+/+ and Sirt1-/- mouse prostate tissues demonstrates that there is a focal atypical intraductal proliferation in prostatic glands of the Sirt1-/- mice, compatible with high grade prostatic intraductal neoplasia (HGPIN). The IHC and relative quantitation of the mouse prostate tissues with Ki67 and AMACR, which are a proliferative and PIN marker respectively, showed an increase of both markers in Sirt1-/- mouse prostate tissue. Preliminary data generated from Sirt1+/+ and Sirt1-/- 3T3 cells suggest that SIRT has a key role in maintaining the mitochondrial healthy status regulating ROS. Sirt1-/- cells undergo a higher oxidative stress, which can lead to cellular damage. We also found mitophagy markers; Beclin1, Bnip3l and LC3 to be overexpressed in Sirt1-/- mouse prostate tissues.

Conclusion and future prospects. These studies suggest SIRT1 inhibits PIN in vivo. The molecular mechanism through which SIRT1 works in a tumor suppressor way is still unknown. We propose a loss of SIRT1 expression may alter the oxidative environment, thereby promoting PIN.

Citation Format: Gabriele Di Sante, Liping Wang, Chenguang Wang, Sara Bisetto, Mathew C Casimiro, Michael Powell, Michael McBurney, Richard Pestell. A novel tumor suppressor role for sirt1 inhibiting mitophagy in prostate mouse tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-133. doi:10.1158/1538-7445.AM2013-LB-133

©2013 American Association for Cancer Research
2013