DOCSLIB.ORG

SPOP Mutation Leads to Genomic Instability in Prostate Cancer Authors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SPOP Mutation Leads to Genomic Instability in Prostate Cancer Authors 1 Title: 2 SPOP mutation leads to genomic instability in prostate cancer 3 4 Authors: 5 Gunther Boysen1,8, Christopher E. Barbieri2,3, Davide Prandi4, Mirjam Blattner1, Sung-Suk Chae1, Arun 6 Dahiya1, Srilakshmi Nataraj1, Dennis Huang1, Clarisse Marotz1, Limei Xu1, Julie Huang1, Paola Lecca4, 7 Sagar Chhangawala5,6, Deli Liu2,6, Pengbo Zhou1, Andrea Sboner1,6,7, Johann S. de Bono8, Francesca 8 Demichelis4,6,7, Yariv Houvras5,9, Mark A. Rubin1,2,3,7 9 10 Affiliations: 11 1 Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, New 12 York, USA 13 2 Department of Urologygy, Weill Cornell Medical College, New York, New York, USA 14 3 Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA 15 4 Centre for Integrative Biologygy, University of Trento, Trento, Italy 16 5 Department of Surgery, Weill Cornell Medical College, New York, New York, USA 17 6 HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill 18 Cornell Medical College, New York, New York, USA 19 7 Institute for Precision Medicine of Weill Cornell Medical College and NewYork-Presbyterian Hospital, 20 New York, New York, USA 21 8 Division of Clinical Studies, The Institute of Cancer Research and the Royal Marsden, London, UK 22 9 Department of Medicine, Weill Cornell Medical College, New York, New York, USA 23 24 These authors contributed equally to this work. 25 G. Boysen, C.E. Barbieri 26 27 These authors jointly directed this work. 28 F. Demichelis, Y. Houvras, M.A. Rubin 29 30 Corresponding authors: 31 C.E. Barbieri: [email protected] 32 M.A. Rubin: [email protected] 33 34 Key words: 35 Prostate Cancer, Cancer Genomics, SPOP, DNA repair 36 37 Disclosure of potential conflict of interest 38 A patent (US Patent Application No: 2013/0331,279) has been issued to Weill Medical College of Cornell 39 University on SPOP mutations in prostate cancer; C.E.B and M.A.R are listed as co-inventors. 1 40 Abstract 41 Genomic instability is a fundamental feature of human cancer often resulting from impaired genome 42 maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving 43 tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate 44 cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in 45 primary prostate cancer, modulates DNA double strand break (DSB) repair, and that SPOP mutation is 46 associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response 47 consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. 48 Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as 49 PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP 50 mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant 51 SPOP may increase response to DNA damaging therapeutics. 52 53 Introduction 54 Genomic instability is a fundamental feature of human cancer, and DNA repair defects resulting in 55 impaired genome maintenance promote pathogenesis of many human cancers1,2. In prostate cancer, 56 structural genomic rearrangements, including translocations (e.g., TMPRSS2-ERG) and copy number 57 aberrations (e.g., 8q gain, 10q23/PTEN loss), are a key mechanism driving tumorigenesis3-9. 58 Whole genome sequencing (WGS) has allowed an unprecedented insight into the alterations 59 underlying cancer. Recently, WGS of treatment naïve, clinically localized prostate cancer revealed a 60 striking abundance of genomic rearrangements, in some samples comparable to the number of 61 rearrangements in metastatic prostate cancer10. Furthermore, the type (intrachromosomal vs. 62 interchromosomal) and complexity of rearrangements in these tumors shows remarkable heterogeneity, 63 potentially suggesting distinct mechanisms of instability in different molecular classes of prostate cancer. 64 However, somatic alterations underlying these phenomena remain unexplained. 2 65 Mutations in SPOP (Speckle-type POZ protein) occur in around 10% of prostate cancers, and 66 represent the most common non-synonymous mutations in primary prostate cancer11. SPOP mutations 67 define a distinct molecular class of prostate cancer; they are mutually exclusive with ETS 68 rearrangements, but display distinct patterns of somatic copy number alterations (SCNAs)11. 69 Here we investigated somatic alterations associated with genomic rearrangements in prostate 70 cancer. We show that SPOP mutation is an early event specifically associated with increased 71 intrachromosomal genomic rearrangements. Mechanistically, in vitro and in vivo data suggest that SPOP 72 participates in repair of DNA double strand breaks (DSB), and SPOP mutation impairs homology- 73 directed repair (HDR), instead promoting error-prone non-homologous end joining (NHEJ). 74 75 Results 76 To nominate somatic events associated with structural genomic rearrangements in clinically 77 localize prostate cancer, we examined WGS data from 55 treatment naïve prostate cancers10 (Figure 78 1A). This analysis revealed a bimodal distribution, with a more common, “low-rearrangement” population, 79 and a less frequent “high-rearrangement” population primarily driven by intrachromosomal 80 rearrangements (deletions, inversions, and tandem duplications), rather than balanced interchromosomal 81 rearrangements (Figure 1B). We then analyzed the association between recurrent somatic alterations 82 (point mutations and somatic copy number alterations [SCNAs]) and number of rearrangements (Figure 83 1C; Figure 1-figure supplements 1,2). Several recurrent deletions, primarily on chromosomes 5q and 6q, 84 were significantly associated with intrachromosomal genomic rearrangements (Figure 1 – figure 85 supplement 1), and these were completely distinct compared to alterations associated with 86 interchromosomal rearrangements (Figure 1 – figure supplement 2). Among recurrent point mutations, 87 only a single lesion – mutation in SPOP – was significantly associated with increased rearrangements 88 (Figure 1C). Consistent with increased intrachromosomal rearrangements, SCNA analysis revealed that 89 SPOP mutant prostate cancers showed significantly higher total copy number alteration burden (Figure 90 1D). 3 91 SPOP mutation frequently co-occurs with specific SCNAs, designating a molecular class of 92 prostate cancer11,12 (Figure 1 – figure supplement 3). Independent analysis of SCNAs from three publicly 93 available datasets comprising 430 tumors,10,11,13 including 47 SPOP mutant prostate cancers, confirmed 94 that the rearrangement-associated deletions (Figure 1-figure supplement 1) were those enriched in 95 SPOP mutant prostate cancer (Figure 1E). When individually comparing SPOP mutations and 96 associated deletions (CHD1 and MAP3K7), we did not observe significant differences in SCNA burden 97 for any one lesion (Figure 1 – figure supplement 4). Analysis of clonality10,14 of specific lesions showed 98 that SPOP mutations were highly clonal compared to loci in the associated deletion peaks, supporting 99 that SPOP mutations precede deletions (Figure 1F). In addition, analysis of dependencies of the lesions 100 supports SPOP mutations preceding CHD1 deletions; no lesions were predicted to precede SPOP 101 mutation (Figure 1 – figure supplement 5). Together, these data nominate a distinct prostate cancer 102 class characterized by early SPOP mutations and genomic instability. We posited that the SPOP 103 mutation impacts genome maintenance and prioritized SPOP for functional studies. 104 105 We explored the functional role of SPOP in vivo, using zebrafish as a rapidly assessable 106 vertebrate model system. SPOP is highly conserved (97.3% identical at the amino acid level between 107 human and zebrafish, Figure 2-figure supplement 1A). Knockdown of Spop by two different splice- 108 blocking morpholinos (MO5, MO7) dramatically impaired brain and eye development as well as 109 decreased overall body size (Figure. 2A,B; Figure 2-figure supplement 1F), resulted in gene expression 110 changes consistent with p53 activation, and apoptosis measured by TUNEL assay (Figure 2C, Figure 2- 111 figure supplement 1E). Microinjection of human SPOP mRNA rescued these phenotypes, confirming 112 specificity of the morpholino effects (Figure 2A-C, Figure 2-figure supplement 1F). To nominate signaling 113 pathways impacted by Spop, we performed transcriptional profiling using RNA-seq on zebrafish with 114 Spop knockdown and ectopic expression of wildtype SPOP (SPOP-wt) and SPOP-F133V, the most 115 commonly mutated residue in prostate cancer (Figure 2D). Consistent with recently reported proteomic 116 data15 and heterodimerization between mutant and wildtype SPOP in our models (Figure 2-figure 4 117 supplement 2), transcriptional responses to SPOP-F133V compared with SPOP-wt and Spop morpholino 118 showed a pattern consistent with dominant negative, selective loss of function; SPOP-F133V correlated 119 with SPOP-wt for some gene sets (Cluster B) and correlated with Spop morpholino for others (Cluster A) 120 (Figure 2D, Figure 2- source data 1). Gene Set Enrichment Analyses (GSEA) revealed gene sets 121 involving DNA repair impacted by modulating SPOP function (Figure 2- source data 2). Notably, the 122 transcriptional response to F133V correlated highly with BRCA1 inactivation (Figure 2E).
Load more

Recommended publications
  • Mutational Landscape Differences Between Young-Onset and Older-Onset Breast Cancer Patients Nicole E
    Mealey et al. BMC Cancer (2020) 20:212 https://doi.org/10.1186/s12885-020-6684-z RESEARCH ARTICLE Open Access Mutational landscape differences between young-onset and older-onset breast cancer patients Nicole E. Mealey1 , Dylan E. O’Sullivan2 , Joy Pader3 , Yibing Ruan3 , Edwin Wang4 , May Lynn Quan1,5,6 and Darren R. Brenner1,3,5* Abstract Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages “deconstructSigs” and “SomaticSignatures” to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young- onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young- onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database.
    [Show full text]
  • Decreased Expression of the SPOP Gene Is Associated with Poor Prognosis in Glioma
    INTERNATIONAL JOURNAL OF ONCOLOGY 46: 333-341, 2015 Decreased expression of the SPOP gene is associated with poor prognosis in glioma DACHENG DING, tao SONG, WU JUN, ZEMING TAN and JIASHENG FANG Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China Received August 23, 2014; Accepted October 3, 2014 DOI: 10.3892/ijo.2014.2729 Abstract. This study suggests that speckle-type POZ protein survival rates of patients with high-grade gliomas are <10% (SPOP) may be a tumor suppressor gene and its prognostic value at 5 years (2). Since current treatment gained little benefit in in human glioma. Real-time quantitative RT-PCR (qRT-PCR), the setting of glioma, greater attention has been paid to the western blotting, and immunohistochemical staining were expression of specific molecular markers with the goal of used to examine SPOP expression in glioma tissues and understanding the main molecular mechanisms of this malig- normal brain (NB) tissues. The relationships between the nancy and determining their possible prognostic significance. SPOP expression levels, the clinicopathological factors, and The speckle-type POZ protein (SPOP) has been identified patient survival were investigated. The molecular mechanisms as an autoantigen in scleroderma patients and a constituent of SPOP expression and its effects on cell viability, migration of nuclear speckles in human cells. SPOP is a 374-amino and invasion were also explored by MTT assay, wound-healing acid protein that contains a C-terminal POZ (poxvirus and assays and Transwell assay. SPOP mRNA and protein levels zinc finger) domain (also known as a BTB domain) and were downregulated in glioma tissues compared to NB.
    [Show full text]
  • Key Pathways in Prostate Cancer with SPOP Mutation Identified By
    Open Medicine 2020; 15: 1039–1047 Research Article Guanxiong Ding#, Jianliang Sun#, Lianhua Jiang#, Peng Gao#, Qidong Zhou, Jianqing Wang*, Shijun Tong* Key pathways in prostate cancer with SPOP mutation identified by bioinformatic analysis https://doi.org/10.1515/med-2020-0237 received December 16, 2019; accepted September 08, 2020 1 Introduction Abstract: Prostate cancer (PCa) is a leading adult Prostate cancer (PCa) is the second most common malignant tumor. Recent research has shown that malignant tumor in men worldwide after lung cancer. A - ( ) speckle type BTB/POZ protein SPOP mutant is the top total of 12,76,106 new cases were reported in 2018, of frequently mutated gene in PCa, which makes it an which 3,58,989 resulted in death (3.8% of all cancer important biomarker. In this paper, we aimed at deaths in men)[1]. The incidence and mortality of PCa identifying critical genes and pathways related to SPOP worldwide are related to the increase in age, and the mutation in PCa. Recent The Cancer Genome Atlas data average age at diagnosis is 66 years. It is worth noting showed that 12% of patients with PCa were SPOP that compared with white men, African Americans have a mutant. There were 1,570 differentially expressed genes, higher morbidity rate, with 158.3 new cases diagnosed per and online enrichment analysis showed that these genes 1,00,000 men, and the mortality rate is about twice that were mainly enriched in metabolism, pathways in cancer of white men [2]. The reason for this difference may be and reactive oxygen species.
    [Show full text]
  • Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: a Feature Selection Approach
    International Journal of Molecular Sciences Article Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: A Feature Selection Approach Simona De Summa 1,* , Antonio Palazzo 2 , Mariapia Caputo 1, Rosa Maria Iacobazzi 3 , Brunella Pilato 1, Letizia Porcelli 3, Stefania Tommasi 1 , Angelo Virgilio Paradiso 4,† and Amalia Azzariti 3,† 1 Molecular Diagnostics and Pharmacogenetics Unit, IRCCS IstitutoTumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] (M.C.); [email protected] (B.P.); [email protected] (S.T.) 2 Laboratory of Nanotechnology, IRCCS IstitutoTumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] 3 Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] (R.M.I.); [email protected] (L.P.); [email protected] (A.A.) 4 Scientific Directorate, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] * Correspondence: [email protected] † Co-senior authors. Abstract: Prostate cancer is one of the most common malignancies in men. It is characterized by a high molecular genomic heterogeneity and, thus, molecular subtypes, that, to date, have not been used in clinical practice. In the present paper, we aimed to better stratify prostate cancer patients through the selection of robust long non-coding RNAs. To fulfill the purpose of the study, a bioinformatic approach focused on feature selection applied to a TCGA dataset was used. In such a way, LINC00668 and long non-coding(lnc)-SAYSD1-1, able to discriminate ERG/not-ERG subtypes, Citation: De Summa, S.; Palazzo, A.; were demonstrated to be positive prognostic biomarkers in ERG-positive patients.
    [Show full text]
  • Comprehensive Biological Information Analysis of PTEN Gene in Pan-Cancer
    Comprehensive biological information analysis of PTEN gene in pan-cancer Hang Zhang Shanghai Medical University: Fudan University https://orcid.org/0000-0002-5853-7754 Wenhan Zhou Shanghai Medical University: Fudan University Xiaoyi Yang Shanghai Jiao Tong University School of Medicine Shuzhan Wen Shanghai Medical University: Fudan University Baicheng Zhao Shanghai Medical University: Fudan University Jiale Feng Shanghai Medical University: Fudan University Shuying Chen ( [email protected] ) https://orcid.org/0000-0002-9215-9777 Primary research Keywords: PTEN, correlated genes, TCGA, GEPIA, UALCAN, GTEx, expression, cancer Posted Date: April 12th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-388887/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/21 Abstract Background PTEN is a multifunctional tumor suppressor gene mutating at high frequency in a variety of cancers. However, its expression in pan-cancer, correlated genes, survival prognosis, and regulatory pathways are not completely described. Here, we aimed to conduct a comprehensive analysis from the above perspectives in order to provide reference for clinical application. Methods we studied the expression levels in cancers by using data from TCGA and GTEx database. Obtain expression box plot from UALCAN database. Perform mutation analysis on the cBioportal website. Obtain correlation genes on the GEPIA website. Construct protein network and perform KEGG and GO enrichment analysis on the STRING database. Perform prognostic analysis on the Kaplan-Meier Plotter website. We also performed transcription factor prediction on the PROMO database and performed RNA-RNA association and RNA-protein interaction on the RNAup Web server and RPISEq.
    [Show full text]
  • Prostate Cancer-Associated SPOP Mutations Enhance Cancer Cell
    Shi et al. Molecular Cancer (2019) 18:170 https://doi.org/10.1186/s12943-019-1096-x RESEARCH Open Access Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1- dependent stress granule assembly Qing Shi1†, Yasheng Zhu2†, Jian Ma3,4†, Kun Chang3,4, Dongling Ding5, Yang Bai5, Kun Gao6, Pingzhao Zhang7, Ren Mo8, Kai Feng1, Xiaying Zhao1, Liang Zhang1, Huiru Sun1, Dongyue Jiao1, Yingji Chen1, Yinghao Sun2, Shi-min Zhao1, Haojie Huang5, Yao Li1*, Shancheng Ren2* and Chenji Wang1* Abstract Background: The gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. Stress granules (SG) assembly is an evolutionarily conserved strategy for survival of cells under stress, and often upregulated in human cancers. We investigated the role of SPOP mutations in aberrant activation of the SG in prostate cancer and explored the relevanve of the mechanism in therapy resistance. Methods: We identified SG nucleating protein Caprin1 as a SPOP interactor by using the yeast two hybrid methods. A series of functional analyses in cell lines, patient samples, and xenograft models were performed to investigate the biological significance and clinical relevance of SPOP regulation of SG signaling in prostate cancer. Results: The cytoplasmic form of wild-type (WT) SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin1. Caprin1 abundance is elevated in SPOP-mutant expressing prostate cancer cell lines and patient specimens. SPOP WT suppresses SG assembly, while the prostate cancer-associated mutants enhance SG assembly in a Caprin1- dependent manner.
    [Show full text]
  • Dual Functions of SPOP and ERG Dictate Androgen Therapy Responses in Prostate Cancer
    ARTICLE https://doi.org/10.1038/s41467-020-20820-x OPEN Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer Tiziano Bernasocchi1,2,11, Geniver El Tekle 1,2,11, Marco Bolis1,11, Azzurra Mutti1, Arianna Vallerga1, Laura P. Brandt3, Filippo Spriano1,2, Tanya Svinkina4, Marita Zoma1,2, Valentina Ceserani1, Anna Rinaldi1, Hana Janouskova1, Daniela Bossi1, Manuela Cavalli1, Simone Mosole1, Roger Geiger 5, Ze Dong6, Cai-Guang Yang 6, Domenico Albino1, Andrea Rinaldi1, Peter Schraml7, Simon Linder8, Giuseppina M. Carbone 1, Andrea Alimonti 1, Francesco Bertoni1, Holger Moch7, Steven A. Carr4, Wilbert Zwart 8, Marianna Kruithof-de Julio 9,10, Mark A. Rubin 3, Namrata D. Udeshi 4 & 1✉ 1234567890():,; Jean-Philippe P. Theurillat Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG pro- motes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.
    [Show full text]
  • Key Genes and Pathways in Measles and Their Interaction with Environmental Chemicals
    4890 EXPERIMENTAL AND THERAPEUTIC MEDICINE 15: 4890-4900, 2018 Key genes and pathways in measles and their interaction with environmental chemicals RONGQIANG ZHANG1*, HUALIN JIANG2,3*, FENGYING LI4, NING SU5, YI DING6, XIANG MAO7, DAN REN2 and JING WANG1 1Department of Epidemiology and Health Statistics, School of Public Health, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi 712046; 2Department of Nursing, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061; 3Department of Medical Education, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032; 4Immunization Department of Center for Disease Control and Prevention of Xianyang, Xianyang, Shaanxi 712046; Departments of 5Radiation Oncology and 6Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China; 7GoDaddy Inc, Sunnyvale, CA 95131, USA Received November 2, 2017; Accepted February 2, 2018 DOI: 10.3892/etm.2018.6050 Abstract. The aim of the present study was to explore key control group and patients with measles (at hospital entry), genes that may have a role in the pathology of measles virus including benzo(a)pyrene (BaP) and tetrachlorodibenzodioxin infection and to clarify the interaction networks between envi- (TCDD). In conclusion, the present study revealed that chemo- ronmental factors and differentially expressed genes (DEGs). kines and environmental chemicals, e.g. BaP and TCDD, may After screening the database of the Gene Expression Omnibus affect the development of measles. of the National Center for Biotechnology Information, the dataset GSE5808 was downloaded and analyzed. A global Introduction normalization method was performed to minimize data incon- sistencies and heterogeneity. DEGs during different stages Measles is a highly contagious infectious disease caused by of measles virus infection were explored using R software the measles virus (MV), which spreads easily through coughs (v3.4.0).
    [Show full text]
  • TRIM28 Protects TRIM24 from SPOP-Mediated Degradation and Promotes Prostate Cancer Progression
    ARTICLE DOI: 10.1038/s41467-018-07475-5 OPEN TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression Ka-wing Fong1, Jonathan C. Zhao1, Bing Song1, Bin Zheng1 & Jindan Yu1,2,3 TRIM24 is an effector substrate of the E3 ubiquitin ligase adaptor SPOP and becomes stabilized in prostate cancer (PCa) with SPOP mutations. However, how TRIM24 protein is 1234567890():,; regulated in the vast majority of SPOP-wildtype PCa is unknown. Here we report TRIM28 as a critical upstream regulator of TRIM24. TRIM28 protein interacts with TRIM24 to prevent its ubiquitination and degradation by SPOP. Further, TRIM28 facilitates TRIM24 occupancy on the chromatin and, like TRIM24, augments AR signaling. TRIM28 promotes PCa cell pro- liferation in vitro and xenograft tumor growth in vivo. Importantly, TRIM28 is upregulated in aggressive PCa and associated with elevated levels of TRIM24 and worse clinical outcome. TRIM24 and AR coactivated gene signature of SPOP-mutant PCa is similarly activated in human PCa with high TRIM28 expression. Taken together, this study provides a novel mechanism to broad TRIM24 protein stabilization and establishes TRIM28 as a promising therapeutic target. 1 Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 2 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 3 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. Correspondence and requests for materials should be addressed to J.Y. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:5007 | DOI: 10.1038/s41467-018-07475-5 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07475-5 ancer genome characterization has recently revealed CRPC, even in those with wild-type SPOP, suggesting other recurrent missense mutations in the Speckle-type POZ essential regulatory pathways19.
    [Show full text]
  • Comprehensive Analysis of Tumour Mutational Burden and Its Clinical Signifcance in Prostate Cancer Lijuan Wang, Shucheng Pan, Binbin Zhu, Zhenliang Yu and Wei Wang*
    Wang et al. BMC Urol (2021) 21:29 https://doi.org/10.1186/s12894-021-00795-7 RESEARCH ARTICLE Open Access Comprehensive analysis of tumour mutational burden and its clinical signifcance in prostate cancer Lijuan Wang, Shucheng Pan, Binbin Zhu, Zhenliang Yu and Wei Wang* Abstract Background: The tumorigenesis of prostate cancer involves genetic mutations. Tumour mutational burden (TMB) is an emerging biomarker for predicting the efcacy of immunotherapy. Results: Single-nucleotide polymorphisms were the most common variant type, and C>T transversion was the most commonly presented type of single-nucleotide variant. The high-TMB group had lower overall survival (OS) than the low-TMB group. TMB was associated with age, T stage and N stage. Functional enrichment analysis of diferentially expressed genes (DEGs) showed that they are involved in pathways related to the terms spindle, chromosomal region, nuclear division, chromosome segregation, cell cycle, oocyte meiosis and other terms associated with DNA mutation and cell proliferation. Six hub genes, PLK1, KIF2C, MELK, EXO1, CEP55 and CDK1, were identifed. All the genes were associated with disease-free survival, and CEP55 and CDK1 were associated with OS. Conclusions: The present study provides a comprehensive analysis of the signifcance of TMB and DEGs and infltrat- ing immune cells related to TMB, which provides helpful information for exploring the signifcance of TMB in prostate cancer. Keywords: Prostate cancer, Tumour mutational burden, Gene, Clinical Background utilization of immunotherapy is still limited by low ef- Prostate cancer ranks as the second most commonly cacy. Some response predictive biomarkers are under diagnosed malignancy in males [1].
    [Show full text]
  • SPOP Suppresses Prostate Cancer Through Regulation of CYCLIN E1 Stability
    Cell Death & Differentiation https://doi.org/10.1038/s41418-018-0198-0 ARTICLE SPOP suppresses prostate cancer through regulation of CYCLIN E1 stability 1 2 1 1 1 1 1 2 Lin-Gao Ju ● Yuan Zhu ● Qiao-Yun Long ● Xue-Jing Li ● Xiang Lin ● Shan-Bo Tang ● Lei Yin ● Yu Xiao ● 2 1 3 1 Xing-Huan Wang ● Lianyun Li ● Lei Zhang ● Min Wu Received: 14 March 2018 / Revised: 25 June 2018 / Accepted: 27 August 2018 © The Author(s) 2018. This article is published with open access Abstract SPOP is one of the important subunits for CUL3/SPOP/RBX1 complex tightly connected with tumorigenesis. However, its exact roles in different cancers remain debatable. Here, we identify CYCLIN E1, as a novel substrate for SPOP. SPOP directly interacts with CYCLIN E1 and specific regulates its stability in prostate cancer cell lines. SPOP/CUL3/RBX1 complex regulates CYCLIN E1 stability through poly-ubiquitination. CDK2 competes with SPOP for CYCLIN E1 interaction, suggesting that SPOP probably regulates the stability of CDK2-free CYCLIN E1. CYCLIN E1 expression rescued proliferation, migration, and tumor formation of prostate cancer cell suppressed by SPOP. Furthermore, we found ’ 1234567890();,: 1234567890();,: SPOP selectively regulates the substrates stability and signaling pathways in prostate cancer and CCRC cell lines, suggesting that complicated mechanisms exist for SPOP to regulate substrate specificity. Altogether, we have revealed a novel mechanism for SPOP in suppressing prostate cancer and provided evidence to show SPOP has dual functions in prostate cancer and CCRC. Introduction studies have established that SPOP forms an ubiquitin E3 ligase complex with cullin 3 (CUL3) and ring-box 1 SPOP was initially identified as a nuclear protein that (ROC1/RBX1), which poly-ubiquitinates substrates with exhibits a speckled localization pattern [1].
    [Show full text]
  • Opposing Effects of Cancer-Type-Specific SPOP Mutants
    ARTICLES Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors Hana Janouskova1,2,15, Geniver El Tekle1–3,15, Elisa Bellini4, Namrata D Udeshi5, Anna Rinaldi1,2, Anna Ulbricht6, Tiziano Bernasocchi1–3, Gianluca Civenni1,2, Marco Losa1,2, Tanya Svinkina5, Craig M Bielski5,14, Gregory V Kryukov5, Luciano Cascione1,2 , Sara Napoli1,2, Radoslav I Enchev6, David G Mutch7 , Michael E Carney8, Andrew Berchuck9, Boris J N Winterhoff10, Russell R Broaddus11, Peter Schraml4, Holger Moch4, Francesco Bertoni1,2, Carlo V Catapano1–3, Matthias Peter6, Steven A Carr5, Levi A Garraway5,12,13, Peter J Wild4 & Jean-Philippe P Theurillat1–3 It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer–associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP–CUL3 substrates that are preferentially degraded by endometrial cancer–associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer–specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.
    [Show full text]