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

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 mamm...

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Autores principales: Tang, Sijie, Lian, Xueqi, Jiang, Jiajia, Cheng, Huiying, Guo, Jiaqian, Huang, Can, Meng, Hong, Li, Xiaohua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649228/
https://www.ncbi.nlm.nih.gov/pubmed/33195208
http://dx.doi.org/10.3389/fcell.2020.573820
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author Tang, Sijie
Lian, Xueqi
Jiang, Jiajia
Cheng, Huiying
Guo, Jiaqian
Huang, Can
Meng, Hong
Li, Xiaohua
author_facet Tang, Sijie
Lian, Xueqi
Jiang, Jiajia
Cheng, Huiying
Guo, Jiaqian
Huang, Can
Meng, Hong
Li, Xiaohua
author_sort Tang, Sijie
collection PubMed
description 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.
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spelling pubmed-76492282020-11-13 Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression Tang, Sijie Lian, Xueqi Jiang, Jiajia Cheng, Huiying Guo, Jiaqian Huang, Can Meng, Hong Li, Xiaohua Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2020-10-26 /pmc/articles/PMC7649228/ /pubmed/33195208 http://dx.doi.org/10.3389/fcell.2020.573820 Text en Copyright © 2020 Tang, Lian, Jiang, Cheng, Guo, Huang, Meng and Li. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Tang, Sijie
Lian, Xueqi
Jiang, Jiajia
Cheng, Huiying
Guo, Jiaqian
Huang, Can
Meng, Hong
Li, Xiaohua
Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression
title Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression
title_full Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression
title_fullStr Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression
title_full_unstemmed Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression
title_short Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression
title_sort tumor suppressive maspin-sensitized prostate cancer to drug treatment through negative regulating androgen receptor expression
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649228/
https://www.ncbi.nlm.nih.gov/pubmed/33195208
http://dx.doi.org/10.3389/fcell.2020.573820
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