» Articles » PMID: 32512734

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

Overview
Journal Cancers (Basel)
Publisher MDPI
Specialty Oncology
Date 2020 Jun 10
PMID 32512734
Citations 6
Authors
Affiliations
Soon will be listed here.
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 results indicate that SPOP deregulation plays a radiosensitizing role in PCa by impairing DDR via downregulation of RAD51 and CHK1.

Citing Articles

Radiotherapy Metastatic Prostate Cancer Cell Lines Treated with Gold Nanorods Modulate miRNA Signatures.

Soares S, Aires F, Monteiro A, Pinto G, Faria I, Sales G Int J Mol Sci. 2024; 25(5).

PMID: 38474003 PMC: 10931958. DOI: 10.3390/ijms25052754.


Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity.

Ye T, Lin A, Qiu Z, Hu S, Zhou C, Liu Z iScience. 2023; 26(7):107045.

PMID: 37448561 PMC: 10336167. DOI: 10.1016/j.isci.2023.107045.


The Influence of miRNAs on Radiotherapy Treatment in Prostate Cancer - A Systematic Review.

Soares S, Guerreiro S, Cruz-Martins N, Faria I, Baylina P, Sales M Front Oncol. 2021; 11:704664.

PMID: 34414113 PMC: 8369466. DOI: 10.3389/fonc.2021.704664.


The establishment of an immunosensor for the detection of SPOP.

Yue S, Sun K, Li S, Liu Y, Zhu Q, Chen Y Sci Rep. 2021; 11(1):12571.

PMID: 34131189 PMC: 8206368. DOI: 10.1038/s41598-021-91944-3.


MicroRNAs as Epigenetic Determinants of Treatment Response and Potential Therapeutic Targets in Prostate Cancer.

Doldi V, El Bezawy R, Zaffaroni N Cancers (Basel). 2021; 13(10).

PMID: 34069147 PMC: 8156532. DOI: 10.3390/cancers13102380.


References
1.
Huang C, Chen H, Lin W, Choo K . Differential expression of speckled POZ protein, SPOP: putative regulation by miR-145. J Biosci. 2014; 39(3):401-13. DOI: 10.1007/s12038-014-9432-1. View

2.
Hatano K, Kumar B, Zhang Y, Coulter J, Hedayati M, Mears B . A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation. Nucleic Acids Res. 2015; 43(8):4075-86. PMC: 4417178. DOI: 10.1093/nar/gkv273. View

3.
El Bezawy R, Cominetti D, Fenderico N, Zuco V, Beretta G, Dugo M . miR-875-5p counteracts epithelial-to-mesenchymal transition and enhances radiation response in prostate cancer through repression of the EGFR-ZEB1 axis. Cancer Lett. 2017; 395:53-62. DOI: 10.1016/j.canlet.2017.02.033. View

4.
Bodgi L, Canet A, Pujo-Menjouet L, Lesne A, Victor J, Foray N . Mathematical models of radiation action on living cells: From the target theory to the modern approaches. A historical and critical review. J Theor Biol. 2016; 394:93-101. DOI: 10.1016/j.jtbi.2016.01.018. View

5.
Chang L, Graham P, Hao J, Bucci J, Cozzi P, Kearsley J . Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy. Cancer Metastasis Rev. 2014; 33(2-3):469-96. DOI: 10.1007/s10555-014-9493-5. View