Abstract
Overactivation of androgen receptor (AR)-mediated signal has been extensively implicated in prostate cancer (CaP) development, progression, and recurrence, which makes it an attractive therapeutic target. Meanwhile, as an endogenous inhibitor of histone deacetylase 1 (HDAC 1), tumor-suppressive mammary serine protease inhibitor (maspin) was reported to sensitize drug-induced apoptosis with a better therapeutic outcome in CaP, but the relationship between AR and maspin remains unclear. In the current study, treatment of 5′-Aza or MS-275/enzalutamide induced poly (ADP-ribose) polymerase (PARP) cleavage and p-H2A.X in CaP cells with an increase of maspin expression but a decrease of AR. Then, treatment with protease inhibitor MG132 did not rescue the above drug-induced loss of AR. In addition, modulation of maspin expression by gene recombinant or siRNA technology showed an inverse correlation between expression of maspin and AR, consequently affecting the AR-regulated downstream gene transcription (e.g., NKX3.1 and TMPRSS2). Bioinformatics analysis of the data extracted from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database also revealed an inverse correlation between low maspin expression and high AR level in advanced CaP. Furthermore, chromatin immunoprecipitation (ChIP) assay using anti-maspin antibody identified that a portion of AR promoter sequence was co-precipitated and presented in the immunoprecipitated complex. Finally, maspin-mediated repression of AR was induced by treatment of MS-275, which promoted enzalutamide treatment efficacy with decrease of prostate-specific antigen (PSA) expression in LNCaP and 22RV1 cells. Taken together, the data not only demonstrated maspin-mediated repression of AR to augment drug anti-tumor activity but also provided in-depth support for combination of HDAC inhibitors with AR antagonist in CaP therapy.
Highlights
Mammary serine protease inhibitor is encoded by the SERPIN B5 gene in humans and belongs to the serine protease inhibitor/non-inhibitor superfamily
Our previous studies found that maspin functioned as endogenous histone deacetylase 1 (HDAC1) inhibitor to prevent higher HDAC1 activity-associated epithelial malignant progress, which was through modulating HDAC1-regulated gene expression including up-regulating cytokeratin 18 (CK18), CK8, and glutathione S-transferase prodidium iodine (PI) (GST pi) and down-regulating hypoxia-induced factor 1α (HIF-1α) (Li et al, 2006, 2011; Lee et al, 2012)
It was well documented that the androgen receptor (AR) antagonist enzalutamide or HDAC inhibitor MS-275 possessed anti-tumor activity
Summary
Mammary serine protease inhibitor (maspin) is encoded by the SERPIN B5 gene in humans and belongs to the serine protease inhibitor/non-inhibitor superfamily. Maspin is expressed predominantly in normal mammary epithelial cells but significantly reduced or absent in most of breast carcinomas, prostate cancer (CaP), gastric malignant tissue, and melanoma cancers, yet is overexpressed in pancreatic, gallbladder, colorectal, and thyroid cancers. The expression of maspin mostly appeared to be correlated with better prognosis clinically in prostate, bladder, lung, gastric, colorectal, head and neck, and thyroid cancers and melanoma (Berardi et al, 2013; Kapoor, 2014). Our previous studies found that maspin functioned as endogenous histone deacetylase 1 (HDAC1) inhibitor to prevent higher HDAC1 activity-associated epithelial malignant progress, which was through modulating HDAC1-regulated gene expression including up-regulating cytokeratin 18 (CK18), CK8, and glutathione S-transferase PI (GST pi) and down-regulating hypoxia-induced factor 1α (HIF-1α) (Li et al, 2006, 2011; Lee et al, 2012). We discovered a novel antitumor mechanism of maspin to repress androgen receptor (AR) transcription, which augmented the treatment efficacy of AR antagonist enzalutamide in prostate cancer
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