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SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair

Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is the most commonly mutated gene in prostate cancer (PCa). Recent evidence reports a role of SPOP in DNA damage response (DDR), indicating a possible impact of SPOP deregulation on PCa radiosensitivity. This study aimed to define t...

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Autores principales: El Bezawy, Rihan, Tripari, Martina, Percio, Stefano, Cicchetti, Alessandro, Tortoreto, Monica, Stucchi, Claudio, Tinelli, Stella, Zuco, Valentina, Doldi, Valentina, Gandellini, Paolo, Valdagni, Riccardo, Zaffaroni, Nadia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352729/
https://www.ncbi.nlm.nih.gov/pubmed/32512734
http://dx.doi.org/10.3390/cancers12061462
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author El Bezawy, Rihan
Tripari, Martina
Percio, Stefano
Cicchetti, Alessandro
Tortoreto, Monica
Stucchi, Claudio
Tinelli, Stella
Zuco, Valentina
Doldi, Valentina
Gandellini, Paolo
Valdagni, Riccardo
Zaffaroni, Nadia
author_facet El Bezawy, Rihan
Tripari, Martina
Percio, Stefano
Cicchetti, Alessandro
Tortoreto, Monica
Stucchi, Claudio
Tinelli, Stella
Zuco, Valentina
Doldi, Valentina
Gandellini, Paolo
Valdagni, Riccardo
Zaffaroni, Nadia
author_sort El Bezawy, Rihan
collection PubMed
description Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is the most commonly mutated gene in prostate cancer (PCa). Recent evidence reports a role of SPOP in DNA damage response (DDR), indicating a possible impact of SPOP deregulation on PCa radiosensitivity. This study aimed to define the role of SPOP deregulation (by gene mutation or knockdown) as a radiosensitizing factor in PCa preclinical models. To express WT or mutant (Y87N, K129E and F133V) SPOP, DU145 and PC-3 cells were transfected with pMCV6 vectors. Sensitivity profiles were assessed using clonogenic assay and immunofluorescent staining of γH2AX and RAD51 foci. SCID xenografts were treated with 5 Gy single dose irradiation using an image-guided small animal irradiator. siRNA and miRNA mimics were used to silence SPOP or express the SPOP negative regulator miR-145, respectively. SPOP deregulation, by either gene mutation or knockdown, consistently enhanced the radiation response of PCa models by impairing DDR, as indicated by transcriptome analysis and functionally confirmed by decreased RAD51 foci. SPOP silencing also resulted in a significant downregulation of RAD51 and CHK1 expression, consistent with the impairment of homologous recombination. Our results indicate that SPOP deregulation plays a radiosensitizing role in PCa by impairing DDR via downregulation of RAD51 and CHK1.
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spelling pubmed-73527292020-07-15 SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair El Bezawy, Rihan Tripari, Martina Percio, Stefano Cicchetti, Alessandro Tortoreto, Monica Stucchi, Claudio Tinelli, Stella Zuco, Valentina Doldi, Valentina Gandellini, Paolo Valdagni, Riccardo Zaffaroni, Nadia Cancers (Basel) Article Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is the most commonly mutated gene in prostate cancer (PCa). Recent evidence reports a role of SPOP in DNA damage response (DDR), indicating a possible impact of SPOP deregulation on PCa radiosensitivity. This study aimed to define the role of SPOP deregulation (by gene mutation or knockdown) as a radiosensitizing factor in PCa preclinical models. To express WT or mutant (Y87N, K129E and F133V) SPOP, DU145 and PC-3 cells were transfected with pMCV6 vectors. Sensitivity profiles were assessed using clonogenic assay and immunofluorescent staining of γH2AX and RAD51 foci. SCID xenografts were treated with 5 Gy single dose irradiation using an image-guided small animal irradiator. siRNA and miRNA mimics were used to silence SPOP or express the SPOP negative regulator miR-145, respectively. SPOP deregulation, by either gene mutation or knockdown, consistently enhanced the radiation response of PCa models by impairing DDR, as indicated by transcriptome analysis and functionally confirmed by decreased RAD51 foci. SPOP silencing also resulted in a significant downregulation of RAD51 and CHK1 expression, consistent with the impairment of homologous recombination. Our results indicate that SPOP deregulation plays a radiosensitizing role in PCa by impairing DDR via downregulation of RAD51 and CHK1. MDPI 2020-06-04 /pmc/articles/PMC7352729/ /pubmed/32512734 http://dx.doi.org/10.3390/cancers12061462 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
El Bezawy, Rihan
Tripari, Martina
Percio, Stefano
Cicchetti, Alessandro
Tortoreto, Monica
Stucchi, Claudio
Tinelli, Stella
Zuco, Valentina
Doldi, Valentina
Gandellini, Paolo
Valdagni, Riccardo
Zaffaroni, Nadia
SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair
title SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair
title_full SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair
title_fullStr SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair
title_full_unstemmed SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair
title_short SPOP Deregulation Improves the Radiation Response of Prostate Cancer Models by Impairing DNA Damage Repair
title_sort spop deregulation improves the radiation response of prostate cancer models by impairing dna damage repair
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352729/
https://www.ncbi.nlm.nih.gov/pubmed/32512734
http://dx.doi.org/10.3390/cancers12061462
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