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

Cancers
Rihan El BezawyNadia Zaffaroni

Abstract

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 res...Continue Reading

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Citations

Oct 8, 2020·International Journal of Molecular Sciences·Masashi Maekawa, Shigeki Higashiyama
Jun 17, 2021·Scientific Reports·Song YueQiubo Yu
Aug 21, 2021·Frontiers in Oncology·Sílvia SoaresRúben Fernandes

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Datasets Mentioned

BETA
GSE147090

Methods Mentioned

BETA
ubiquitination
transgenic
xenografts
nuclear translocation
transfection
gene knockdown
PCR
X-ray
mice

Software Mentioned

ACT
GSEA
lumi
GraphPad Prism
limma Bioconductor
SmART Plan

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