Preclinical evaluation of combined antineoplastic effect of DLC1 tumor suppressor protein and suberoylanilide hydroxamic acid on prostate cancer cells

• Published in: Biochemical and biophysical research communications 2012-04, Vol.420 (2), p.325-330
• Main Authors: Zhou, Xiaoling, Yang, Xu-Yu, Popescu, Nicholas C.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis; BALB 3T3 Cells; Cell Line, Tumor; Combined Modality Therapy; DLC1; DNA Methylation - drug effects; Drug Evaluation, Preclinical; GTPase-Activating Proteins - genetics; Histone Deacetylase Inhibitors - therapeutic use; Humans; Hydroxamic Acids - therapeutic use; Inhibition prostate tumor growth in vivo; Male; Mice; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - therapy; RhoA activity; SAHA; Transduction, Genetic; Tumor suppressor gene; Tumor Suppressor Proteins - genetics; Vorinostat
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2012.02.158

► Prostate tumor cells lacking DLC1 expression are sensitive to SAHA. ► Re-expression of DLC1 and SAHA inhibit prostate tumor cells growth in vivo. ► Antitumor effect correlated with apoptosis and reduction of RhoA activity. ► RhoA appears to be an important target for SAHA. ► Treatment with SAHA might be therapeutically beneficial for prostate cancer. Deleted in liver cancer (DLC1), a tumor suppressor gene in multiple cancers, is recurrently down regulated or inactivated by epigenetic mechanisms in primary prostate carcinomas (PCAs). In this study the methylation and acetylation profile of the DLC1 promoter region was examined in three PCA cell lines with low or undetectable DLC1 expression: LNCaP, its derivative C4-2B-2, and 22Rv1. Two histone deacetylase inhibitors (HDAC), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) induced histone acetylation of the DLC1 promoter in all three lines. DLC1 promoter methylation and deacetylation were detected in LNCaP and C4-2B-2 cells while in 22Rv1 cells DLC1 is silenced by deacetylation. Treatment with SAHA or TSA efficiently increased DLC1 expression in all lines, particularly in 22Rv1 cells, and activated the DLC1 promoter through the same Sp1 sites. The 22Rv1 cell line was selected to evaluate the efficacy of combined DLC1 transduction and SAHA treatment on tumor growth in athymic mice. Individually, DLC1 transduction and SAHA exposure reduced the tumor size by 75–80% compared to controls and in combination almost completely inhibited tumor growth. The antitumor effect was associated with the induction of apoptosis and inhibition of RhoA activity. SAHA alone significantly reduced RhoA activity, showing that this RhoGTPase is a target for SAHA. These results, obtained with a reliable preclinical in vivo test, predict that combined therapeutic agents targeting the pathways governing DLC1 function and HDAC inhibitors may be beneficial in management of prostate cancer.