Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression

Sijie Tang; Xueqi Lian; Jiajia Jiang; Huiying Cheng; Jiaqian Guo; Can Huang; Hong Meng; Xiaohua Li

doi:10.3389/fcell.2020.573820

Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression

Front Cell Dev Biol. 2020 Oct 26:8:573820. doi: 10.3389/fcell.2020.573820. eCollection 2020.

Authors

Sijie Tang¹, Xueqi Lian¹, Jiajia Jiang¹, Huiying Cheng¹, Jiaqian Guo¹, Can Huang¹, Hong Meng², Xiaohua Li^{1

3

4}

Affiliations

¹ The AoYang Cancer Institute, Jiangsu University, Suzhou, China.
² Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Detroit, MI, United States.
³ The Laboratory of Clinical Genomics, Hefei KingMed Diagnostics Laboratory, Hefei, China.
⁴ National Center for Gene Testing Technology Application & Demonstration (Anhui), Hefei, China.

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.

Keywords: HDAC inhibitor; androgen receptor; castration-resistant prostate cancer; chemotherapy; maspin.