Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG

Wasmuth, Elizabeth V.; Hoover, Elizabeth; Antar, Albert; Klinge, Sebastian; Chen, Yu; Sawyers, Charles L.

doi:10.1073/pnas.1922159117

Cited by 39 publications

(63 citation statements)

References 58 publications

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“…The androgen receptor (AR) is a key transcription factor that promotes luminal cell fates and AR activity is necessary for the growth of all early stage prostate tumors. Several studies indicate that ERG can cooperate with AR in promoting luminal cell fate [11,12,13]. In contrast to these findings, we and others have shown that expression of ERG in the immortalized-normal prostate cell line RWPE1 does not promote luminal epithelial differentiation, but rather promotes the seemingly opposite phenotypes of migration, invasion, and epithelial to mesenchymal transition (EMT) [14,15,16,17,18].…”

Section: Introductioncontrasting

confidence: 61%

Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells

2021

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The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function.

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Section: Introductioncontrasting

confidence: 61%

Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells

2021

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“…Despite the initial efficacy of ADT, the surviving cells show a persistent and often, an amplified AR signaling axis. Numerous studies have shown that an amplification of ligand-independent AR signaling occurs due to numerous crosstalk between AR and parallel non-AR signaling pathways [17,20,42,[64][65][66] . Therefore, strategies to suppress both AR and non-AR signaling would be needed to ultimately suppress the outgrowth of CRPC cells.…”

Section: Ar Signaling Hormone Deprivation and Crpc Outgrowthmentioning

confidence: 99%

“…In a more recent publication, this group also showed that gene polymorphisms in antioxidant enzymes correlate with the efficacy of ADT, clearly implicating the importance of oxidative stress with CRPC outgrowth [160] . In this respect, ligand-receptor interactions between androgens and AR is a major regulator of redox signaling in PCa cells [66,[161][162][163] and in dictating treatment resistance [162] . Therefore, it is now well accepted that sudden changes in androgen levels, such as during hormone deprivation, can drastically alter cellular homeostasis to increase oxidative stress, ROS production and dysregulated redox signaling networks.…”

Section: Is There a Therapeutic Benefit Of Antioxidants In Crpc Progrmentioning

confidence: 99%

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

Mondal¹,

Narwani²,

Notta³

et al. 2020

CDR

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Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

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“…We therefore examined the extent to which the findings of AR dependence of genes encoding kinases and phosphatases derived from LNCaP cells can be extrapolated to other AR-positive cell lines, such as VCaP. VCaP cells express the TMPRSS2-ERG gene fusion and show AR gene amplification, which can each impact the composition of the AR cistrome (Waltering et al 2009, Yu et al 2010, Makkonen et al 2011, Wasmuth et al 2020. Analyses of two publically available and independent AR ChIP-Seq data sets derived from VCaP cells (Massie et al 2011, Asangani et al 2014) employing the same selection criteria used on LNCaP cell data (i.e.…”

Section: Transcriptional Control By Ar Over Kinases and Phosphatasesmentioning

confidence: 99%

AR-dependent phosphorylation and phospho-proteome targets in prostate cancer

Venkadakrishnan

Ben-Salem

Heemers

2020

Endocrine-Related Cancer

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Prostate cancer (CaP) is the second leading cause of cancer-related deaths in Western men. Because androgens drive CaP by activating the androgen receptor (AR), blocking AR’s ligand activation, known as androgen deprivation therapy (ADT), is the default treatment for metastatic CaP. Despite an initial remission, CaP eventually develops resistance to ADT and progresses to castration-recurrent CaP (CRPC). CRPC continues to rely on aberrantly activated AR that is no longer inhibited effectively by available therapeutics. Interference with signaling pathways downstream of activated AR that mediate aggressive CRPC behavior may lead to alternative CaP treatments. Developing such therapeutic strategies requires a thorough mechanistic understanding of the most clinically relevant and druggable AR-dependent signaling events. Recent proteomics analyses of CRPC clinical specimens indicate a shift in the phosphoproteome during CaP progression. Kinases and phosphatases represent druggable entities, for which clinically tested inhibitors are available, some of which are incorporated already in treatment plans for other human malignancies. Here, we reviewed the AR-associated transcriptome and translational regulon, and AR interactome involved in CaP phosphorylation events. Novel and for the most part mutually exclusive AR-dependent transcriptional and post-transcriptional control over kinase and phosphatase expression was found, with yet other phospho-regulators interacting with AR. The multiple mechanisms by which AR can shape and fine-tune the CaP phosphoproteome were reflected in diverse aspects of CaP biology such as cell cycle progression and cell migration. Furthermore, we examined the potential, limitations and challenges of interfering with AR-mediated phosphorylation events as alternative strategy to block AR function during CaP progression.

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Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG

Cited by 39 publications

References 58 publications

Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells

Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

AR-dependent phosphorylation and phospho-proteome targets in prostate cancer

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