CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation

Rasool, Reyaz ur; Natesan, Ramakrishnan; Deng, Qu; Aras, Shweta; Lal, Priti; Effron, Samuel Sander; Mitchell-Velasquez, Erick; Posimo, Jessica M.; Carskadon, Shannon; Baca, Sylvan C.; Pomerantz, Mark; Siddiqui, Javed; Schwartz, Lauren E.; Lee, Dong Hoon; Palanisamy, Nallasivam; Narla, Goutham; Den, Robert B.; Freedman, Matthew L.; Brady, Donita C.; Asangani, Irfan A.

doi:10.1158/2159-8290.cd-19-0189

Cited by 93 publications

(101 citation statements)

References 58 publications

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“…We noted that AR itself and several canonical AR target genes were located in proximity to SE regions in LNCaP cells, and likewise that a large proportion of SEs were occupied by AR (Fig. 5b, c), in agreement with a prior report 47 . Across all AR-occupied enhancers, we observed global decreases in AR and H3K27ac signal upon PRMT1 knockdown or furamidine treatment ( Fig. 5d-g; Supplementary Fig.…”

Section: Prmt1 Suppression Leads To Loss Of Ar Genomic Occupancy At Lsupporting

confidence: 92%

A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer

Tang

Metaferia

Nogueira

et al. 2020

Preprint

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Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR/Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates recruitment of AR to genomic target sites and inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. Additionally, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.

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Section: Prmt1 Suppression Leads To Loss Of Ar Genomic Occupancy At Lsupporting

confidence: 92%

A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer

Tang

Metaferia

Nogueira

et al. 2020

Preprint

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“…2B). This was accompanied by a concomitant decrease in the levels of phosphoSer81-AR (pAR), an active chromatin-bound form of AR (Rasool et al, 2019). More importantly, the ACE2 transcript and the protein levels were also downregulated in the steroid-deprived cells.…”

Section: Ar Regulates Tmprss2 and Ace2 Expression In Human Prostate Amentioning

confidence: 99%

Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

Deng

Rasool

Russell

et al. 2020

Preprint

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The COVID-19 pandemic is expected to have an adverse effect on the progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm and associated oncogenic signaling. Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and co-receptor TMPRSS2 by androgen in mouse tissues and human prostate and lung cell lines. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. In an overexpression model, and the prostate and lung cells, Camostat – a TMPRSS2 inhibitor, blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction. Thus providing evidence for the first time a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike protein, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens such as enzalutamide/AR-PROTAC, or Camostat treatment attenuated the SARS-CoV-2 S-mediated entry in lung and prostate cells. Together, our preclinical data provide a strong rationale for clinical evaluations of the TMPRSS2 inhibitors, androgen-deprivation therapy and androgen receptor antagonists alone or in combination with anti-viral drugs as early as clinically possible to prevent inflammation driven COVID-19 progression.

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“…A previous study showed that inhibition of CDK2 suppressed PCa metastases by inactivating PI3K/Akt signaling (40). CDK5, CDK6, CDK7, and CDK9 can suppress CRPC through AR inactivation (41)(42)(43)(44). In addition, CDK inhibitors are currently being evaluated in clinical trials (45).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Kinase Expression Related to Increased Migration of PC-3M Cells Using Global Comparative Phosphoproteome Analysis

Gao

Kwon

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Prostate cancer (PCa) is the second-most commonly occurring cancer among men, worldwide. Although the mechanisms associated with the progression of castration-resistant prostate cancer (CRPC) have been widely studied, the mechanism associated with more distant metastases from the bone remains unknown. This study aimed to characterize potential pathogenic kinases associated with highly metastatic PCa, that may regulate phosphorylation in extensively involved and diverse signaling pathways that are associated with the development of various cancers. Materials and Methods: A mass spectrometry (MS)based comparative phosphoproteome strategy was utilized to identify differentially expressed kinases between the highly aggressive PCa cell-lines PC-3 and PC-3M. Results: Among 2,968 phosphorylation sites in PCa cells, 151 differently expressed phosphoproteins were identified. Seven motifs:-SP- ,-SxxE- ,-PxS- ,-PxSP- ,-SxxK- ,-SPxK-, and-SxxxxxP-were found to be highly expressed in PC-3M cells. Based on these motifs, the kinases p21-activated kinase (PAK)2, Ste20-like kinase (SLK), mammalian Ste20-like kinase (MST)4, mitogenactivated kinase kinase (MAP2K)2, and A-Raf proto-oncogene serine/threonine kinase (ARAF) were up-regulated in PC-3M cells. Conclusion: PAK2, SLK, MST4, MAP2K2, and ARAF are kinases that are potentially associated with the progression of increased migration in PC-3M cells and may represent molecule regulators or drug targets for highly metastatic PCa therapy. Prostate cancer (PCa) is the second-most commonly occurring cancer among men, worldwide (1, 2). According to the latest report by the American Cancer Society, in 2020, 191,930 new cases of PCa will be diagnosed and 33,330 individuals will die from PCa, in the United States (3). Unlike other types of cancers, PCa grows very slowly and may not cause symptoms for years, until the cancer cells metastasize out of the prostate, developing to advanced PCa (4, 5). This characteristic has limited most cases of PCa being recognized and treated during the early stages, and prostate-specific antigen technology began to be applied to the detection of primary-stage PCa in 1994 (6, 7). Because PCa is an androgen-dependent disease (8), androgen deprivation therapy is the standard therapy for the initial stages of advanced PCa; however, treatment can eventually result in the development of castration-resistant PCa (CRPC) (9). Androgen receptor (AR) inhibition remains a key factor in CRPC therapies. Metastatic CRPC (mCRPC) develops when PCa cells spread to other parts of the body, where they can grow and spread, even under medical treatment (10). According to the "seed and soil" theory, proposed by Paget (11), PCa spreads in the bloodstream as "seeds", which settle in specific organs, which represent 543 This article is freely accessible online.

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CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation

Cited by 93 publications

References 58 publications

A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer

A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer

Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

Characterization of Kinase Expression Related to Increased Migration of PC-3M Cells Using Global Comparative Phosphoproteome Analysis

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