The Pioneering Role of GATA2 in Androgen Receptor Variant Regulation Is Controlled by Bromodomain and Extraterminal Proteins in Castrate-Resistant Prostate Cancer

Chaytor, Lewis; Simcock, Matthew; Nakjang, Sirintra; Heath, Richard A.; Walker, Laura; Robson, Craig; Jones, Dominic; Gaughan, Luke

doi:10.1158/1541-7786.mcr-18-1231

Cited by 17 publications

(20 citation statements)

References 45 publications

(92 reference statements)

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“…Interestingly, the GATA2 cistrome shares a consistent overlap with bromodomain and extra terminal (BET) proteins and is codependent for DNA binding; in line with this observation, BET inhibitors compromise GATA2 activity in CRPC cells [292]. These observations support the use of BET inhibitors in CRPC patients overexpressing GATA2 [292].…”

Section: Novel Therapies For Prostate Cancermentioning

confidence: 79%

“…The study of AR-variant transcriptome is in part dependent upon FOXA1 [655]. A recent study showed that GATA2 is a critical regulator of AR-Vs [292]. Interestingly, the GATA2 cistrome shares a consistent overlap with bromodomain and extra terminal (BET) proteins and is codependent for DNA binding; in line with this observation, BET inhibitors compromise GATA2 activity in CRPC cells [292].…”

Section: Novel Therapies For Prostate Cancermentioning

confidence: 99%

“…Furthermore, BET inhibitors act as blocking competitors of the transcription factor GATA2, playing an essential role in the regulation of AR-Vs expression, and, through this mechanism, these drugs may have a potential role in the treatment of CRPC expressing AR-Vs [292].…”

Section: Most Recurrent Genetic Abnormalities Observed In Prostatementioning

confidence: 99%

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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: Novel Therapies For Prostate Cancermentioning

confidence: 79%

Section: Novel Therapies For Prostate Cancermentioning

confidence: 99%

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Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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“…Moreover, GATA2 directly promotes the expression of the AR before and after androgen stimulation . In cell lines derived from an aggressive, castrate‐resistant (antiandrogen‐resistant) prostate cancer, GATA2 is a critical regulator of the transcriptional activity of a constitutively active AR variant; an interaction with BET proteins facilitates GATA2 chromatin occupancy and promotes the expression of cell‐cycle‐related genes targeted by GATA2 and regulated by the AR variant—thus favoring cell proliferation and disease progression …”

Section: Gata2mentioning

confidence: 99%

GATA factor transcriptional activity: Insights from genome‐wide binding profiles

Romano

Miccio

2019

IUBMB Life

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The members of the GATA family of transcription factors have homologous zinc fingers and bind to similar sequence motifs. Recent advances in genome-wide technologies and the integration of bioinformatics data have led to a better understanding of how GATA factors regulate gene expression; GATA-factor-induced transcriptional and epigenetic changes have now been analyzed at unprecedented levels of detail.Here, we review the results of genome-wide studies of GATA factor occupancy in human and murine cell lines and primary cells (as determined by chromatin immunoprecipitation sequencing), and then discuss the molecular mechanisms underlying the mediation of transcriptional and epigenetic regulation by GATA factors. K E Y W O R D S

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“…Many previous studies have attempted to find target molecules for CRPC therapy. GATA2 (GATA-binding protein 2) and FOXA1 (forkhead box A1) have been proposed as important regulators of AR splice variant-driven transactivation that has been shown to be associated with CRPC [ 5 ]. GATA2 induces tumorigenicity and resistance to chemotherapy by giving rise to the GATA2–IGF2 (insulin like growth factor 2) axis in CRPC [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription

Yang

Jin

Park

et al. 2020

Cancers

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Androgen deprivation therapy eventually leads to the development of castration-resistant prostate cancer (CRPC). Here, we demonstrate for the first time that the histone H3K4 methyltransferase SETD1A is a major regulator for the proliferation of metastatic CRPC (mCRPC). The expression of SETD1A was significantly correlated with the survival rate of patients with prostate cancer. SETD1A, which is expressed at a higher level in mCRPC than in primary prostate cancer cells, promotes the expression of FOXM1, a gene encoding a cell proliferation-specific transcription factor. SETD1A is recruited to the promoter region of FOXM1 (forkhead box M1) upon binding to E2F1, a protein that regulates the transcription of FOXM1 and contributes to the trimethylation of H3K4 in the FOXM1 promoter region. In addition, SETD1A is essential for the expression of stem cell factor (e.g., OCT4, octamer-binding transcription factor 4) and stem cell formation in mCRPC, suggesting the importance of SETD1A expression in mCRPC tumor formation. Notably, poor prognosis is associated with high expression of the SETD1A–FOXM1 pair in clinical data sets. Therefore, our study suggests that SETD1A plays an important role in the proliferation of mCRPC by regulating FOXM1 transcription.

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The Pioneering Role of GATA2 in Androgen Receptor Variant Regulation Is Controlled by Bromodomain and Extraterminal Proteins in Castrate-Resistant Prostate Cancer

Cited by 17 publications

References 45 publications

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

GATA factor transcriptional activity: Insights from genome‐wide binding profiles

SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription

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