The Amino-terminal Domain of the Androgen Receptor Co-opts Extracellular Signal-regulated Kinase (ERK) Docking Sites in ELK1 Protein to Induce Sustained Gene Activation That Supports Prostate Cancer Cell Growth

Rosati, Rita; Patki, Mugdha; Chari, Venkatesh; Selvakumar, Dakshnamurthy; McFall, Thomas; Saxton, Janice; Kidder, Benjamin L.; Shaw, Peter E.; Ratnam, Manohar

doi:10.1074/jbc.m116.745596

Cited by 16 publications

(32 citation statements)

References 58 publications

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“…To delineate the mechanism behind its distinct expression in these cells we analyzed the AIRE promoter region for the binding sites of various other transcription factors. Recently, transcription factor Elk-1 which belongs to Ets family of transcription factors has been shown to be associated with prostate cancer progression 21 , 22 . Elk-1 is also known to be accessory and supportive for AR transcriptional signaling 23 .…”

Section: Resultsmentioning

confidence: 99%

AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment

et al. 2018

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Early stage prostate cancers are dependent on androgens for their growth and survival and androgen withdrawal causes them to regress. Progressive prostate cancers eventually acquire androgen independence rendering anti-androgen therapy ineffective. However, the factors leading to this have not been adequately addressed. This study shows that AIRE finds differential expression in androgen-dependent and -independent prostate cancer cells. AIRE expression is more in androgen-independent cells due to its regulation by transcription factor Elk-1. These enhanced levels of AIRE modulate the prostate tumor microenvironment by transcriptionally activating a malignancy gene IL-6 in androgen-independent cells. Additionally, AIRE prevents the cancer cells from anticancer drug-induced death and enhances their invasiveness. Moreover, AIRE by modulating the cytokine milieu skews the tumor-associated macrophage polarization towards M2 phenotype with increased CD206 and CD163 expression. Subcutaneous mouse model of prostate cancer revealed AIRE+/+ mice forming a palpable tumor and presents lymphadenopathy however, only a small benign tumor is observed in AIRE−/− mice and lymph nodes appear normal in size. In conclusion, our findings suggest AIRE as a probable factor in promoting prostate cancer progression.

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Section: Resultsmentioning

confidence: 99%

AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment

et al. 2018

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“…Under androgen deprivation, we found that the most enriched motif corresponded to ELK1 (Fig 8A). ELK1 is an ETS transcription factor and AR co-regulator that promotes growth in prostate cancer cells and regulates ligand-independent recruitment of AR to chromatin through interaction with the AR NTD [23, 24]. Interestingly, also enriched under androgen deprivation, as well as with androgen treatment, were several other members of the ETS family of transcription factors (Fig 8A and S12A Fig).…”

Section: Resultsmentioning

confidence: 99%

“…ELK1 is an ETS transcription factor that controls AR transcriptional activity and promotes prostate cancer progression [20, 23, 24]. ELK1 has also been shown to interact directly with the AR ligand-independent N-terminal transcriptional activation domain [23, 24]. Given the increase in H3K27 acetylation at the MAOA promoter with MED19 overexpression, it is possible that MED19, in conjunction with ELK1, could promote recruitment of HATs, such CBP and p300, which are also known AR co-regulators [10–12].…”

Section: Discussionmentioning

confidence: 99%

“…ETS binding motifs are enriched at AR occupancy sites in prostate cancer cells, and multiple ETS family members are upregulated in prostate cancer [18–22]. In particular, the ETS family member ELK1 was found to interact with the N-terminal domain (NTD) of AR and directly regulate its recruitment to chromatin in prostate cancer cells [23, 24]. Inhibition of ELK1 reduces expression of AR target genes and suppresses prostate cancer cell growth [23, 24].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, the ETS family member ELK1 was found to interact with the N-terminal domain (NTD) of AR and directly regulate its recruitment to chromatin in prostate cancer cells [23, 24]. Inhibition of ELK1 reduces expression of AR target genes and suppresses prostate cancer cell growth [23, 24].…”

Section: Introductionmentioning

confidence: 99%

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MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

Weber

Ruoff

Garabedian

2019

Preprint

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Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined H3K27 acetylation genome-wide. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 and genomic sites occupied by MED19 and AR are enriched for ELK1, a transcription factor that binds the AR N-terminus to promote select AR-target gene expression. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.Author summaryProstate cancer is one of the most common cancers worldwide, and androgen hormones are essential for prostate cancer growth. Androgens exert their effects through a protein called the androgen receptor (AR), which turns on and off genes that regulate prostate cancer growth. Powerful drugs that block AR action by lowering androgen levels – so-called androgen deprivation therapy - are used to treat prostate cancer patients, and these yield initial success in reducing tumor growth. However, over time, tumors circumvent androgen deprivation therapy and patients relapse; in many cases, this occurs because AR becomes re-activated. The factors responsible for re-activating AR and promoting growth under androgen deprivation are not well understood. Here, we demonstrate that a subunit of the Mediator transcriptional regulatory complex, called MED19, promotes growth of prostate cancer cells under low androgen conditions, mimicking the ability of tumors to grow under androgen deprivation in prostate cancer patients. MED19 promotes androgen-independent growth by working with a transcription factor that interacts with AR, called ELK1, to induce the expression of genes regulated by AR that promote prostate cancer growth. This study provides important insight into how prostate cancer cells can maintain growth under androgen deprivation through MED19.

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The ternary complex factor protein ELK1 is an independent prognosticator of disease recurrence in prostate cancer

et al. 2019

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Background: Both hormone sensitive and castration-and enzalutamide-resistant prostate cancers (PCa) depend on the ternary complex factor (TCF) protein ELK1 to serve as a This is the author manuscript accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

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The Amino-terminal Domain of the Androgen Receptor Co-opts Extracellular Signal-regulated Kinase (ERK) Docking Sites in ELK1 Protein to Induce Sustained Gene Activation That Supports Prostate Cancer Cell Growth

Cited by 16 publications

References 58 publications

AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment

AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

The ternary complex factor protein ELK1 is an independent prognosticator of disease recurrence in prostate cancer

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