SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Blattner, Mirjam; D, Liu; Robinson, Brian D.; Huang, Dennis; Poliakov, Anton; Gao, Dong; Nataraj, Srilakshmi; Deonarine, Lesa D.; Augello, Michael A.; Sailer, Verena; Ponnala, Lalit; Ittmann, Michael; Chinnaiyan, Arul M.; Sboner, Andrea; Chen, Yu; Rubin, Mark A.; Barbieri, Christopher E.

doi:10.1016/j.ccell.2017.02.004

Cited by 168 publications

(196 citation statements)

References 51 publications

(106 reference statements)

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“…Consistent with these findings, SPOP mutations were previously implicated in androgen signaling because both AR and AR coactivators undergo deregulation in the presence of SPOP mutations [84–86]. AR signaling was more frequently altered in metastatic samples, most often by amplifications or mutations of AR , which were essentially absent in localized prostatic cancers [87].…”

Section: Molecular Characteristics Of Prostatic Cancersupporting

confidence: 62%

“…A recent study demonstrated that CHD1 is a putative synthetic-essential gene in PTEN -deficient cancers, and CHD1 depletion profoundly and specifically suppresses cell proliferation in PTEN -deficient prostate cancers [118]. Another recent study showed that SPOP mutations activate both PIK3/MTOR and AR signaling pathways, effectively uncoupling the normal negative-feedback mechanism between these two pathways [86]. …”

Section: Molecular Characteristics Of Prostatic Cancermentioning

confidence: 99%

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Prostatic cancers: understanding their molecular pathology and the 2016 WHO classification

Inamura

2018

Oncotarget

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Accumulating evidence suggests that prostatic cancers represent a group of histologically and molecularly heterogeneous diseases with variable clinical courses. In accordance with the increased knowledge of their clinicopathologies and genetics, the World Health Organization (WHO) classification of prostatic cancers has been revised. Additionally, recent data on their comprehensive molecular characterization have increased our understanding of the genomic basis of prostatic cancers and enabled us to classify them into subtypes with distinct molecular pathologies and clinical features. Our increased understanding of the molecular pathologies of prostatic cancers has permitted their evolution from a poorly understood, heterogeneous group of diseases with variable clinical courses to characteristic molecular subtypes that allow the implementation of personalized therapies and better patient management. This review provides perspectives on the new 2016 WHO classification of prostatic cancers as well as recent knowledge of their molecular pathologies. The WHO classification of prostatic cancers will require additional revisions to allow for reliable and clinically meaningful cancer diagnoses as a better understanding of their molecular characteristics is obtained.

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Section: Molecular Characteristics Of Prostatic Cancersupporting

confidence: 62%

Section: Molecular Characteristics Of Prostatic Cancermentioning

confidence: 99%

Prostatic cancers: understanding their molecular pathology and the 2016 WHO classification

Inamura

2018

Oncotarget

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“…We observed MAPK driver mutations in HRAS (p.Q61K, 2%) and BRAF (p.G469A, 1%). Putative dominant negative SPOP mutations were present in 5% of cases (Barbieri et al, 2012; Blattner et al, 2017). ETS gene family activations were mutually exclusive with activating alterations in the RAS/MAPK pathway members ( P = 0.01, Fisher’s exact test) and with inactivation of SPOP and CHD1 (Barbieri et al, 2012; Burkhardt et al, 2013; Huang et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Quigley

Dang

Zhao

et al. 2018

Cell

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569

663

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While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

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“…Approximately 10% of prostate cancer patients harbor SPOP mutations (Barbieri et al , ). In this subtype of prostate cancers, both AKT and AR signaling are aberrantly activated (An et al , ; Geng et al , ; Blattner et al , ; Zhang et al , ). Currently, strategies for effectively treating this unique subclass of patients remain to be explored.…”

Section: Resultsmentioning

confidence: 99%

“…The gene encoding SPOP is the most frequently mutated gene in human primary prostate cancers (Barbieri et al , ; Cancer Genome Atlas Research Network, ). Functional studies show that ectopic expression of the most frequent SPOP‐mutant F133V in human prostatic cells or knock‐in in the mouse prostate results in aberrant activation of AR and AKT‐mTORC1 signaling (An et al , , ; Geng et al , ; Blattner et al , ; Zhang et al , ). Most importantly, the Cancer Genome Atlas (TCGA) data demonstrate that SPOP‐mutated prostate cancers exhibit the highest AR activity among all molecular subtypes of prostate cancer examined (Cancer Genome Atlas Research Network, ).…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of AKT ‐m TOR and AR signaling by targeting HDAC 3 in PTEN ‐ or SPOP ‐mutated prostate cancer

Yan

Yang

et al. 2018

EMBO Mol Med

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AKT‐mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine‐63‐chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN‐deficient and SPOP‐mutated prostate cancer cells in culture, patient‐derived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single‐agent targeting of HDAC3 in prostate cancer.

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SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Cited by 168 publications

References 51 publications

Prostatic cancers: understanding their molecular pathology and the 2016 WHO classification

Prostatic cancers: understanding their molecular pathology and the 2016 WHO classification

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Dual inhibition of AKT ‐m TOR and AR signaling by targeting HDAC 3 in PTEN ‐ or SPOP ‐mutated prostate cancer

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