Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function

Pinz, Sophia; Unser, Samy; Buob, Dominik; Fischer, Philipp; Jobst, Belinda; Rascle, Anne

doi:10.1093/nar/gkv188

Cited by 33 publications

(64 citation statements)

References 95 publications

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“…Future animal studies are needed to compare the efficacy of the different STAT5 SH2 compounds in reducing cyst growth in ADPKD models. Alternatively, HDAC6 inhibition was recently shown to be effective in reducing cyst growth in murine PKD 32 ; this is particularly relevant to this study because HDAC inhibition reduces STAT5 transcriptional activity 33 , therefore use of selective HDAC inhibitors can be employed as an alternative strategy to inhibit atypical STAT5-initiated signalling.…”

Section: Discussionmentioning

confidence: 99%

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

Fragiadaki

Lannoy

Themanns

et al. 2017

Kidney International

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Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signalling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here we present an siRNA JAK-STAT focused screen revealing a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, STAT5b). Amongst these we selected to study the GH-GHR-STAT5-axis because of its known role as a regulator of growth in non-renal tissues. We show that STAT5 loss of function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth in vitro. To study whether STAT5 is abnormally activated in vivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both. To test whether forced activation of STAT5 can modulate proliferation of renal cells in vivo, irrespective of Pkd1 status, we overexpressed growth hormone (GH). GH mice showed increased STAT5 activity in renal epithelial cells, correlating with de-novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitations, revealed that STAT5 transcriptionally activated cyclin D1 in GH-stimulated renal epithelial but not control cells, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated GH in Pkd1 nl/nl mice. Collectively, our data identify the GH-STAT5 signalling axis as a novel therapeutic target in ADPKD.

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Section: Discussionmentioning

confidence: 99%

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

Fragiadaki

Lannoy

Themanns

et al. 2017

Kidney International

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“…In vitro , Brd2 directly promotes transcription on a chromatinized template by acting as a chromatin remodeler (Leroy et al, 2008). Additionally, Brd2 can bind both TBP and Mediator, both of which are normally absent from bivalent promoters (Peng et al, 2006; Pinz et al, 2015). Thus, future studies will be directed toward understanding how H2A.Z.1ub inhibits gene activation through antagonism of Brd2.…”

Section: Discussionmentioning

confidence: 99%

H2A.Z.1 Monoubiquitylation Antagonizes BRD2 to Maintain Poised Chromatin in ESCs

et al. 2016

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SUMMARY Histone variant H2A.Z occupies the promoters of active and poised, bivalent genes in ESCs to regulate developmental programs, yet how it contributes to these contrasting states is poorly understood. Here, we investigate the function of H2A.Z.1 mono-ubiquitylation (H2A.Z.1ub) by mutation of the PRC1 target residues (H2A.Z.1K3R3). We show that H2A.Z.1K3R3 is properly incorporated at target promoters in murine ESCs (mESCs), however, loss of mono-ubiquitylation leads to de-repression of bivalent genes, loss of Polycomb binding, and to faulty lineage commitment. Using quantitative proteomics, we find that tandem bromodomain proteins, including the BET family member Brd2, are enriched in H2A.Z.1 chromatin. We further show that Brd2 is gained at de-repressed promoters in H2A.Z.1K3R3 mESCs whereas Brd2 inhibition restores gene silencing at these sites. Together, our study reveals an antagonistic relationship between H2A.Z.1ub and Brd2 to regulate the transcriptional balance at bivalent genes to enable proper execution of developmental programs.

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“…CISH has been shown to be overexpressed in breast cancer and stimulates proliferation by activating the ERK pathway (34). STAT5-induced CISH transcription has been well characterized (10,30,35), making it a robust model for initial analyses. To assess chromatin compaction at the CISH promoter, various histone proteins were assessed by ChIP over a time course of PRL treatment.…”

Section: Prl Treatment Induces Chromatin Decompaction and Promotes Bimentioning

confidence: 99%

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells

Schauwecker

Kim

Licht

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuThe hormone prolactin (PRL) contributes to breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the transcription factor STAT5 results in the up-regulation of numerous genes implicated in breast cancer pathogenesis. However, the molecular mechanisms that enable STAT5 to access the promoters of these genes are not well understood. Here, we show that PRL signaling induces chromatin decompaction at promoter DNA, corresponding with STAT5 binding. The chromatin-modifying protein high mobility group nucleosomal binding domain 2 (HMGN2) specifically promotes STAT5 accessibility at promoter DNA by facilitating the dissociation of the linker histone H1 in response to PRL. Knockdown of H1 rescues the decrease in PRL-induced transcription following HMGN2 knockdown, and it does so by allowing increased STAT5 recruitment. Moreover, H1 and STAT5 are shown to function antagonistically in regulating PRL-induced transcription as well as breast cancer cell biology. While reduced STAT5 activation results in decreased PRL-induced transcription and cell proliferation, knockdown of H1 rescues both of these effects. Taken together, we elucidate a novel mechanism whereby the linker histone H1 prevents STAT5 binding at promoter DNA, and the PRL-induced dissociation of H1 mediated by HMGN2 is necessary to allow full STAT5 recruitment and promote the biological effects of PRL signaling.In the mammary gland, signals from the polypeptide hormone prolactin (PRL) are essential for normal development (1-4), and these physiological effects are mediated through the homologous transcription factors signal transducer and activator of transcription 5a and 5b (referred to as STAT5) (5). PRL signals by binding to the PRL receptor (PRLR), 2 a transmembrane receptor of the cytokine receptor superfamily. Binding of PRL to the PRLR results in the activation of STAT5 via phosphorylation by the tyrosine kinase Janus kinase 2 (JAK2) (6 -8). Phosphorylated STAT5 dimerizes, and the active STAT5 dimers translocate to the nucleus. In the nucleus, STAT5 recognizes and binds to consensus elements in the DNA, which induces the expression of STAT5 target genes (9).PRL-induced STAT5 activation results in the up-regulation of many pro-proliferative genes (10 -12). Although essential for proper mammary gland development, aberrant PRL signaling and STAT5 activation also contribute to breast cancer pathogenesis. Transgenic mice that overexpress PRL in the mammary epithelium develop mammary tumors, which can be either estrogen receptor-positive or -negative (13). In epidemiologic studies, women with elevated serum PRL are at an increased risk of developing breast cancer (14 -17). PRL also enhances the proliferation, motility, and survival of breast cancer cells (18 -20). Similarly, overexpression of STAT5 in the mammary gland of transgenic mice results in mammary tumor development (21), whereas hemizygous los...

show abstract

Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function

Cited by 33 publications

References 95 publications

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

H2A.Z.1 Monoubiquitylation Antagonizes BRD2 to Maintain Poised Chromatin in ESCs

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells

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