ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Cai, Ling; Tsai, Yi-Hsuan; Wang, Ping; Wang, Jun; Li, Dongxu; Fan, Huitao; Zhao, Yilin; Bareja, Rohan; Lu, Rui; Wilson, Elizabeth M.; Sboner, Andrea; Whang, Young E.; Zheng, Deyou; Parker, Joel S.; Earp, H. Shelton; Wang, Gang Greg

doi:10.1016/j.molcel.2018.08.029

Cited by 71 publications

(95 citation statements)

References 71 publications

(122 reference statements)

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“…BET proteins directly interact with the NTD of the AR ( 90 ). Moreover, BRD4 has numerous shared DNA binding loci with full-length AR and AR-V7 ( 90 , 91 ). With FOXA1, BRD4 and AR-V7 bind to canonical AR target genes, but with ZFX they bind to non-canonical genes related to cell cycle, autophagy, and WNT signaling ( 91 ).…”

Section: Bet Proteinsmentioning

confidence: 99%

“…Moreover, BRD4 has numerous shared DNA binding loci with full-length AR and AR-V7 ( 90 , 91 ). With FOXA1, BRD4 and AR-V7 bind to canonical AR target genes, but with ZFX they bind to non-canonical genes related to cell cycle, autophagy, and WNT signaling ( 91 ). Accordingly, BET inhibitors downregulate the expression of AR target genes, as well as MYC ( 90 , 91 ).…”

Section: Bet Proteinsmentioning

confidence: 99%

“…With FOXA1, BRD4 and AR-V7 bind to canonical AR target genes, but with ZFX they bind to non-canonical genes related to cell cycle, autophagy, and WNT signaling ( 91 ). Accordingly, BET inhibitors downregulate the expression of AR target genes, as well as MYC ( 90 , 91 ). BET inhibitors also decrease AR-V7 levels by regulating alternative splicing ( 92 , 93 ).…”

Section: Bet Proteinsmentioning

confidence: 99%

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Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

et al. 2020

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The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.

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Section: Bet Proteinsmentioning

confidence: 99%

Section: Bet Proteinsmentioning

confidence: 99%

Section: Bet Proteinsmentioning

confidence: 99%

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Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

et al. 2020

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“…Although AR-V7 and AR-FL share common chromatin binding sites, AR-V7 also displayed distinct binding sites by interacting with different coregulators/repressors [ 35 ]. For example, key mediators such as HOXB13 and ZFX can mediate AR-V7 function [ 36 , 37 ], and AR-V7 prefers binding to open chromatin regions in prostate cancer cells [ 37 , 38 ]. It is, therefore, not surprising that AR-V7 drives a distinct transcriptional program in an AR-FL-indifferent manner in an earlier study [ 33 ].…”

Section: Summary Of Ar-vs Characterized So Farmentioning

confidence: 99%

Regulation of androgen receptor variants in prostate cancer

Zhu

Luo

2020

Asian Journal of Urology

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Aberrant activation of androgen receptor (AR) signaling occurs in patients treated with AR-targeted therapies, contributing to the development of castration-resistant prostate cancer (CRPC) and therapeutic resistance. Over the past decade, many AR variants (AR-Vs) have been identified in prostate cancer cell lines and clinical CRPC specimens. These AR-Vs lack the COOH-terminal ligand-binding domain (LBD), and may mediate constitutively active AR signaling acquired following AR-targeting therapies. AR splice variant-7 (AR-V7), one of the most well characterized AR-Vs, can be reliably measured in tissue and liquid biopsy specimens, and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies (NHT) such as abiraterone and enzalutamide in men with metastatic CRPC (mCRPC). Given the important clinical implication of AR-Vs, this short review will focus on studies addressing how AR-Vs are regulated in prostate cancer. With regard to the molecular origin of AR-Vs, it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR signaling. Therapeutic targeting of the AR axis may result in active transcription of the AR gene, elevated activities of certain components of the mRNA splicing machinery, as well as AR genomic alterations, all of which may explain the molecular origin of AR-Vs. Although a unified hypothesis is currently lacking, existing data suggest that elevated expression of AR-Vs, which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed, is driven by both genomic and epigenomic features acquired in the development of CRPC.

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“…Recent papers investigated the genomic binding of AR-FL and AR-V7 in CRPC cells and identified AR-FL and AR-V7 co-bound sites preferentially at ARE within enhancers. Interestingly, an additional subset of genes was bound and regulated uniquely by AR-V7 [68,69] . ZFX represents a crucial partner for AR-V7 binding at promoters, and the non-canonical gene expression program regulated by the two transcription factors promotes malignant growth of CRPC cells and is associated with poor prognosis [68] .…”

Section: Genomic Features Of Ar-dependent Resistancementioning

confidence: 99%

Evolution of the prostate cancer genome towards resistance

Lorenzin¹,

Demichelis²

2019

JTGG

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The clinical behavior of prostate cancer is highly heterogeneous, with most patients diagnosed with localized disease that successfully responds to surgery or radiotherapy or that can be followed by active surveillance. However, a fraction of men will relapse after initial treatment and eventually progress to an aggressive resistant form with metastasis spreading and high mortality, a state referred to as castration resistant prostate cancer (CRPC). The technological advances in next generation sequencing have enabled the deep genomic and epigenomic characterization of both the hormone naïve and CRPC states, leading to the definition of molecular subclasses of prostate cancer that could inform the clinicians on therapeutic strategies. These studies also shed light on the mechanisms driving resistance to therapy. CRPCs adapt to androgen receptor (AR) signaling impairment-which follows first-line therapies as androgen deprivation or AR targeting-by restoring the nuclear receptor signaling by means of multiple mechanisms. Alternatively, tumor cells might become resistant to targeted therapies by exploiting lineage plasticity and activating alternative pathways. This review will discuss the main mechanisms leading to the emergence of resistance to therapy in prostate cancer patients in the context of genomic and molecular features of CRPC and on their causal role in the development of resistance.

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ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Cited by 71 publications

References 71 publications

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

Regulation of androgen receptor variants in prostate cancer

Evolution of the prostate cancer genome towards resistance

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