BRD4 regulates key transcription factors that drive epithelial–mesenchymal transition in castration-resistant prostate cancer

Shafran, Jordan S.; Jafari, Naser; Casey, Allison N.; Győrffy, Balázs; Denis, Gerald V.

doi:10.1038/s41391-020-0246-y

Cited by 32 publications

(34 citation statements)

References 42 publications

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“…On the other hand, SLUG and SNAIL have been reported to inhibit each other in oral cancer [Nakamura et al, 2018] and breast cancer [Ganesan et al, 2015]. The effect of SLUG on EMP dynamics can also be influenced by upstream regulators of SLUG such as RNF8, YAP, C/EBPδ, miR-151, CBP, RCP, HDAC1, HDAC3, BRD4 and STAT3 [Cheng et al, 2020;Chesnelong et al, 2019;Kuang et al, 2020;Wang et al, 2020;Daugaard et al, 2017;Jury et al, 2020;Dai et al, 2020;Hwang et al, 2017;Hu et al, 2020;Shafran et al, 2020]. Moreover, SLUG may be involved in feedback loops with one or more p63 isoforms [Srivastava et al, 2018;Dang et al, 2016;Herfs et al, 2010] that can also enable a partial EMT [Jolly et al, 2017a;Westcott et al, 2020].…”

Section: Discussionmentioning

confidence: 99%

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Subbalakshmi

Sahoo

Biswas

et al. 2020

Preprint

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Epithelial-mesenchymal plasticity comprises of reversible transitions among epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal phenotypes, and underlies various aspects of aggressive tumor progression such as metastasis, therapy resistance and immune evasion. The process of cells attaining one or more hybrid E/M phenotypes is termed as partial EMT. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either fully epithelial or mesenchymal state. Thus, identifying regulators of hybrid E/M phenotypes is essential to decipher the rheostats of phenotypic plasticity and consequent accelerators of metastasis. Here, using a computational systems biology approach, we demonstrate that SLUG (SNAIL2) – an EMT-inducing transcription factor – can inhibit cells from undergoing a complete EMT and thus stabilizing them in hybrid E/M phenotype(s). It expands the parametric range enabling the existence of a hybrid E/M phenotype, thereby behaving as a phenotypic stability factor (PSF). Our simulations suggest that this specific property of SLUG emerges from the topology of the regulatory network it forms with other key regulators of epithelial-mesenchymal plasticity. Clinical data suggests that SLUG associates with worse patient prognosis across multiple carcinomas. Together, our results indicate that SLUG can stabilize hybrid E/M phenotype(s).

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Section: Discussionmentioning

confidence: 99%

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Subbalakshmi

Sahoo

Biswas

et al. 2020

Preprint

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“… 10 , 17 , 28 , 29 , 30 For example, loss of BRD4, but not of BRD2 or BRD3, causes R-loop-induced DNA damage. 31 Clinical studies have validated the efficacy of targeting BRD4, and not BRD2 or BRD3, in glioma, 32 breast cancer, 33 and prostate cancer 34 therapy.…”

Section: Brd4: the Most Studied Bet Proteinmentioning

confidence: 99%

BRD4: An emerging prospective therapeutic target in glioma

Yang

Xiao

et al. 2021

Molecular Therapy - Oncolytics

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Despite advances in treatment, the prognosis for glioma patients remains poor. Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) protein family, plays an important role in controlling oncogene expression and genome stability. In recent years, numerous BRD4 inhibitors have entered clinical trials and achieved exciting results in tumor treatment. Recent clinical studies have shown that BRD4 expression in glioma is significantly higher than in the adjacent normal brain tissue. BRD4 inhibitors effectively penetrate the blood-brain barrier and target glioma tumor tissues but have little effect on normal brain tissues. Thus, BRD4 is a target for the treatment of glioma. In this study, we discuss the progress in the use of BRD4 inhibitors for glioma treatment, their mechanism of action, and their broad potential clinical application.

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“…BRD4 has been reported to promote tumor growth and epithelial‐to‐mesenchymal transition in several cancers including prostate cancer, hepatocellular carcinoma, renal cell carcinoma, basal‐like breast cancer (BLBC), and so forth 37,40,50 . The key TFs, contributing to the activation of mesenchymal phenotype, are SNAIL, TWIST and zinc‐finger E‐box binding (ZEB) factors.…”

Section: Brd4 In Cellular Transdifferentiationmentioning

confidence: 99%

“…The key TFs, contributing to the activation of mesenchymal phenotype, are SNAIL, TWIST and zinc‐finger E‐box binding (ZEB) factors. BRD4 was found to regulate the expression of SNAIL1 and SNAIL2 in castration‐resistant prostate cancer 37 . Furthermore, Tian and coworkers 38 showed that in the case of chronic obstructive and interstitial lung diseases, airway remodeling is the common cause that triggers chronic epithelial injury followed by the release of growth factors and morphogenetic cytokines, particularly TGF‐β.…”

Section: Brd4 In Cellular Transdifferentiationmentioning

confidence: 99%

Emerging Roles of Bromodomain Protein 4 in Regulation of Stem Cell Identity

et al. 2021

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Understanding the mechanism of fate decision and lineage commitment is the key step for developing novel stem cell applications in therapeutics. This process is coordinately regulated through systematic epigenetic reprogramming and concomitant changes in the transcriptional landscape of the stem cells. One of the bromo- and extra-terminal domain (BET) family member proteins, bromodomain protein 4 (BRD4), performs the role of epigenetic reader and modulates gene expression by recruiting other transcription factors and directly regulating RNA polymerase II elongation. Controlled gene regulation is the critical step in maintenance of stem cell potency and dysregulation may lead to tumor formation. As a key transcriptional factor and epigenetic regulator, BRD4 contributes to stem cell maintenance in several ways. Being a druggable target, BRD4 is an attractive candidate for exploiting its potential in stem cell therapeutics. Therefore, it is crucial to elucidate how BRD4, through its interplay with pluripotency transcriptional regulators, control lineage commitment in stem cells. Here, we systemically review the role of BRD4 in complex gene regulatory network during three specific states of stem cell transitions: cell differentiation, cell reprogramming and transdifferentiation. A thorough understanding of BRD4 mediated epigenetic regulation in the maintenance of stem cell potency will be helpful to strategically control stem cell fates in regenerative medicine.

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BRD4 regulates key transcription factors that drive epithelial–mesenchymal transition in castration-resistant prostate cancer

Cited by 32 publications

References 42 publications

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

BRD4: An emerging prospective therapeutic target in glioma

Emerging Roles of Bromodomain Protein 4 in Regulation of Stem Cell Identity

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