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

Published on Jun 4, 2020in Cancers6.126
· DOI :10.3390/CANCERS12061462
Rihan El Bezawy3
Estimated H-index: 3
,
Martina Tripari1
Estimated H-index: 1
(University of Liverpool)
+ 9 AuthorsNadia Zaffaroni66
Estimated H-index: 66
Sources
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.
📖 Papers frequently viewed together
28 Citations
References32
Newest
Background Radiotherapy is one of the main treatment options for non-metastatic prostate cancer (PCa). Although treatment technical optimization has greatly improved local tumor control, a considerable fraction of patients still experience relapse due to the development of resistance. Radioresistance is a complex and still poorly understood phenomenon involving the deregulation of a variety of signaling pathways as a consequence of several genetic and epigenetic abnormalities. In this context, c...
28 CitationsSource
#1Yiping Dong (Xi'an Jiaotong University)H-Index: 6
#2Dan Zhang (Xi'an Jiaotong University)H-Index: 3
Last. Suxia Han (Xi'an Jiaotong University)H-Index: 16
view all 10 authors...
Speckle-type POZ protein (SPOP) plays an important role in maintaining genome stability. Disability or mutation of the SPOP gene has been reported to contribute to prostate cancer incidence and prognosis. However, the functions of SPOP in lung cancer remain poorly understood, especially in lung adenocarcinoma (LUAD). Here, we found that SPOP affects the LUAD cell response to radiation by regulating the DNA damage response (DDR) pathway. SPOP is widely expressed in lung cancer cell lines, and SPO...
7 Citations
#1Kim Hjorth-Jensen (UCPH: University of Copenhagen)H-Index: 1
Last. Amilcar Flores-Morales (UCPH: University of Copenhagen)H-Index: 33
view all 8 authors...
: Mutations in SPOP, the gene most frequently point-mutated in primary prostate cancer, are associated with a high degree of genomic instability and deficiency in homologous recombination repair of DNA but the underlying mechanisms behind this defect are currently unknown. Here we demonstrate that SPOP knockdown leads to spontaneous replication stress and impaired recovery from replication fork stalling. We show that this is associated with reduced expression of several key DNA repair and replic...
13 CitationsSource
#1Rihan El BezawyH-Index: 3
#2Denis CominettiH-Index: 14
Last. Paolo GandelliniH-Index: 25
view all 12 authors...
Abstract Radiotherapy is one of the main treatment choices for non-metastatic prostate cancer (PCa), although development of radioresistance limits its effectiveness. Mounting evidence supports the ability of microRNAs to interfere with different radioresistance-associated pathways, suggesting their potential as radiosensitizers. Here, we demonstrate that reconstitution of miR-875-5p, whose expression is down-regulated in PCa clinical samples and directly correlates with that of E-cadherin, was ...
57 CitationsSource
#1Nicolas MottetH-Index: 39
#2Joaquim Bellmunt (Harvard University)H-Index: 88
Last. Philip CornfordH-Index: 26
view all 22 authors...
Abstract Objective To present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on screening, diagnosis, and local treatment with curative intent of clinically localised prostate cancer (PCa). Evidence acquisition The working panel performed a literature review of the new data (2013–2015). The guidelines were updated and the levels of evidence and/or gra...
1,813 CitationsSource
#1Mirjam Blattner (Cornell University)H-Index: 11
#2Deli Liu (Cornell University)H-Index: 10
Last. Christopher E. Barbieri (Cornell University)H-Index: 31
view all 17 authors...
Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP dr...
77 CitationsSource
Biochemical failure after primary external beam radiotherapy for prostate cancer is common, and a significant proportion of these failures are due to local residual or recurrent disease. Early or delayed palliation using androgen deprivation therapy is the most common approach. Although a conservative approach is appropriate for many individuals, selected patients would benefit from retreatment with curative intent. We review the pertinent literature on salvage of locally recurrent prostate canc...
23 CitationsSource
#1Anna C. Groner (Harvard University)H-Index: 16
#2Laura Cato (Harvard University)H-Index: 9
Last. Myles Brown (Harvard University)H-Index: 112
view all 22 authors...
Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Ex...
117 CitationsSource
#1Larry Bodgi (French Institute of Health and Medical Research)H-Index: 8
#2Aurélien Canet (UCBL: Claude Bernard University Lyon 1)H-Index: 3
Last. Nicolas Foray (French Institute of Health and Medical Research)H-Index: 30
view all 6 authors...
Abstract Cell survival is conventionally defined as the capability of irradiated cells to produce colonies. It is quantified by the clonogenic assays that consist in determining the number of colonies resulting from a known number of irradiated cells. Several mathematical models were proposed to describe the survival curves, notably from the target theory. The Linear-Quadratic (LQ) model, which is to date the most frequently used model in radiobiology and radiotherapy, dominates all the other mo...
40 CitationsSource
#1Pijun Gong (Xi'an Jiaotong University)H-Index: 1
#2Tingting Zhang (Xi'an Jiaotong University)H-Index: 11
Last. Jer Tsong Hsieh (UTSW: University of Texas Southwestern Medical Center)H-Index: 61
view all 4 authors...
Radiation therapy prior to surgery has increasingly become the standard of care for locally advanced prostate cancer, however tumor radioresistance remains a major clinical problem. While restoration of microRNA-145 (miR-145) expression reduces chemoradioresistance in glioblastoma and suppress prostate cancer proliferation, migration and invasion, the role of miR-145 in response to radiation therapy for prostate cancer is still unknown. The aim of this study was to investigate the role of miR-14...
30 CitationsSource
Cited By1
Newest
#1Valentina DoldiH-Index: 8
#2Rihan El BezawyH-Index: 3
Last. Nadia ZaffaroniH-Index: 66
view all 3 authors...
Prostate cancer (PCa) is the second most common tumor in men worldwide, and the fifth leading cause of male cancer-related deaths in western countries. PC is a very heterogeneous disease, meaning that optimal clinical management of individual patients is challenging. Depending on disease grade and stage, patients can be followed in active surveillance protocols or undergo surgery, radiotherapy, hormonal therapy, and chemotherapy. Although therapeutic advancements exist in both radiatiotherapy an...
Source
Speckle-type BTB/POZ protein (SPOP) is a substrate recognition receptor of the cullin-3 (CUL3)/RING type ubiquitin E3 complex. To date, approximately 30 proteins have been identified as ubiquitinated substrates of the CUL3/SPOP complex. Pathologically, missense mutations in the substrate-binding domain of SPOP have been found in prostate and endometrial cancers. Prostate and endometrial cancer-associated SPOP mutations lose and increase substrate-binding ability, respectively. Expression of thes...
Source