The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival

McClurg, Urszula L.; Azizyan, Mahsa; Dransfield, Daniel T.; Namdev, Nivedita; Chit, Nay C T H; Nakjang, Sirintra; Robson, Craig

doi:10.18632/oncotarget.25167

Cited by 20 publications

(18 citation statements)

References 64 publications

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“…Galaterone is a new androgen-targeting agent that acts inhibiting CYP17: this agent antagonizes the AR, inducing a degradation of both full-length and AR-V7 [205]. Furthermore, Galaterone targets two homologous deubiquitinating enzymes—USP12 and USP46—which control the AR-AKT-MDM2-P53 signaling pathway [206]. Phase I and II studies with Galatereone (ARMOR 1 and ARMOR2) have shown a decline in PSA levels in 49% of treated patients [207].…”

Section: Most Recurrent Genetic Abnormalities Observed In Prostatementioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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Section: Most Recurrent Genetic Abnormalities Observed In Prostatementioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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“…The E1-UAF1-USP complex is recruited to the viral origin and is necessary for efficient replication of the HPV genome ( 11 – 14 ). While the UAF1-USP12 and UAF1-USP46 complexes regulate histone deubiquitination ( 15 ) and the cell survival- and growth-promoting Akt pathway ( 16 – 20 ), the UAF1-USP1 complex is involved in the Fanconi anemia (FA) DNA repair pathway ( 21 ). HPV genome replication depends on the activation of both the ATM and ATR arms of the cellular DNA damage response (DDR) pathway ( 22 – 27 ).…”

Section: Introductionmentioning

confidence: 99%

Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes

Orav

Gagnon

Archambault

2019

mBio

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Human papillomaviruses (HPVs) are important pathogens with a significant medical burden. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism. In this report, we provide evidence that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 deubiquitinating enzyme complex, a member of the Fanconi anemia DNA damage response pathway, is required for the completion of the bidirectional theta replication of the HPV11 genome and the subsequent initiation of the unidirectional replication. We show that unidirectional replication proceeds via theta structures and is supported by the cellular Bloom helicase, which interacts directly with E1 and whose engagement in HPV11 replication requires UAF1-USP1 activity. We propose that the unidirectional replication of the HPV11 genome initiates from replication fork restart events. These findings suggest a new role for the Fanconi anemia pathway in HPV replication. IMPORTANCE Human papillomaviruses (HPVs) are important pathogens that replicate their double-stranded circular DNA genome in the nucleus of infected cells. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism, and the onset of viral replication requires the engagement of cellular DNA damage response pathways. In this study, we showed that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 complex is necessary for the completion of bidirectional replication and the subsequent initiation of the unidirectional replication mechanism. Our results suggest HPVs may use the cellular Fanconi anemia DNA damage pathway to achieve the separation of daughter molecules generated by bidirectional theta replication. Additionally, our results indicate that the unidirectional replication of the HPV genome is initiated from restarted bidirectional theta replication forks.

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“…USP12 has been shown to regulate the ubiquitination level of histone H2A and H2B [23] and to deubiquitinate AR and MDM2, which regulate the p53-MDM2-AR-AKT signaling network. In addition, USP12 promotes cell survival, proliferation, tumorigenesis, and cell cycle progression by upregulating BMI-1, c-Myc, and cyclin D2 [24][25][26][27]. Our multiplex RT-PCR results showed that USP12 expression was increased by DEHP in A2780 cells, and thus, the above-mentioned findings of its influence on cell cycle progression and proliferation suggest that it may induce POF by influencing oocyte maturation.…”

Section: Discussionmentioning

confidence: 52%

Differential Expression of DUB Genes in Ovarian Cells Treated with Di-2-Ethylhexyl Phthalate

Lee

Park

Choi

et al. 2020

IJMS

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Premature ovarian failure (POF) is defined as loss of ovarian function in women less than 40 years of age. The causes of POF are diverse and include environmental factors. Di-2-ethylhexyl phthalate (DEHP) is one factor that may cause POF. The ubiquitin-proteasome system maintains intracellular balance by promoting or inhibiting protein degradation. To investigate the differential expressions of deubiquitinating enzyme (DUB) genes in patients with POF, we developed two in vitro POF models by treating A2780 or OVCAR5 with DEHP. Using these models, a multiplex RT-PCR system for DUB genes was applied to identify biomarkers by comparing expression patterns and DUB mRNA levels; multiplex RT-PCR results were validated by qRT-PCR and Western blotting analyses. Observed differential expression levels of several DUB genes including USP12, COPS5, ATXN3L, USP49, and USP34 in A2780 and OVCAR5 cells at the mRNA and protein levels suggest that they should be investigated as potential biomarkers of POF.

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The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival

Cited by 20 publications

References 64 publications

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes

Differential Expression of DUB Genes in Ovarian Cells Treated with Di-2-Ethylhexyl Phthalate

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