HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth

Medler, Terry R.; Craig, Justin M.; Fiorillo, Alyson A.; Feeney, Yvonne B.; Harrell, J. Chuck; Clevenger, Charles V.

doi:10.1158/1541-7786.mcr-16-0109

Cited by 37 publications

(27 citation statements)

References 53 publications

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“…HMGN2 was also shown to promote breast cancer growth in response to prolactin. In this system, HMGN2 reduces the binding of linker histone H1 to chromatin regulatory regions, thereby enhancing STAT5 accessibility to promoter DNA, ultimately leading to increased proliferation of breast cancer cells [54,55]. Further analysis showed that the K2 residue of HMGN2 was deacetylated in primary breast tumors but highly acetylated in normal human breast tissue, implying that targeting HMGN2 deacetylation may be a viable treatment for this type of breast cancer [55].…”

Section: Cancermentioning

confidence: 99%

Biological Functions of HMGN Chromosomal Proteins

Nanduri

Furusawa

Bustin

2020

IJMS

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Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can lead to disease. The high mobility group N (HMGN) is a family of nucleosome binding proteins that preferentially binds to chromatin regulatory sites including enhancers and promoters. HMGN proteins are ubiquitously expressed in all vertebrate cells potentially affecting chromatin function and epigenetic regulation in multiple cell types. Here, we review studies aimed at elucidating the biological function of HMGN proteins, focusing on their possible role in vertebrate development and the etiology of disease. The data indicate that changes in HMGN levels lead to cell type-specific phenotypes, suggesting that HMGN optimize epigenetic processes necessary for maintaining cell identity and for proper execution of specific cellular functions. This manuscript contains tables that can be used as a comprehensive resource for all the English written manuscripts describing research aimed at elucidating the biological function of the HMGN protein family.

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Section: Cancermentioning

confidence: 99%

Biological Functions of HMGN Chromosomal Proteins

Nanduri

Furusawa

Bustin

2020

IJMS

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“…PRL-induced genes were previously identified by our laboratory through global RNA profiling (42,43), and the genes immediate early response 3 (IER3) and pleckstrin homologylike domain, family A, member 2 (PHLDA2) were chosen for further analysis based on their breast cancer relevance (see "Discussion"). PRL treatment resulted in increased expression of CISH, IER3, and PHLDA2 here (Fig.…”

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...

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“…Most of the cell studies were performed to understand the function of a particular protein of interest. Excluding studies that link functional changes to KDAC activity on histones (and therefore exert a functional effect via gene regulation rather than a change in target acetylation status), these studies rely on one or more tools to manipulate either the level of KDAC expression or activity in the cell, and then measure the change in acetylation of the target protein, usually by immunoblotting using an acetylation specific antibody 31‐82 . (Note that we have only included studies that utilized human cells.…”

Section: Approaches For Kdac Substrate Identificationmentioning

confidence: 99%

“…First, many of these experiments have utilized KDAC inhibitors to reduce the amount of deacetylation, and then looked for changes in acetylation levels of putative substrate proteins 31‐39,83‐85 . While experimentally convenient, essentially all available inhibitors are capable of inhibiting multiple KDACs, due to the high degree of similarity between the KDAC active sites.…”

Section: Approaches For Kdac Substrate Identificationmentioning

confidence: 99%

“…KDAC6‐tubulin is the best established non‐histone KDAC‐substrate pair 104 . KDAC6 has been shown by multiple groups in many different ways to deacetylate tubulin at lysine 40 (K40) both in vitro and in vivo 31‐33,55,84,88,105 . It has been proposed that the acetylation/deacetylation of tubulin at this site serves to regulate the stability of microtubules and cilia 6,7,106 .…”

Section: Putative Kdac‐substrate Pairsmentioning

confidence: 99%

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Critical review of non‐histone human substrates of metal‐dependent lysine deacetylases

Toro

Watt

2020

FASEB j.

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Lysine acetylation is a posttranslational modification that occurs on thousands of human proteins, most of which are cytoplasmic. Acetylated proteins are involved in numerous cellular processes and human diseases. Therefore, how the acetylation/deacetylation cycle is regulated is an important question. Eleven metal‐dependent lysine deacetylases (KDACs) have been identified in human cells. These enzymes, along with the sirtuins, are collectively responsible for reversing lysine acetylation. Despite several large‐scale studies which have characterized the acetylome, relatively few of the specific acetylated residues have been matched to a proposed KDAC for deacetylation. To understand the function of lysine acetylation, and its association with diseases, specific KDAC‐substrate pairs must be identified. Identifying specific substrates of a KDAC is complicated both by the complexity of assaying relevant activity and by the non‐catalytic interactions of KDACs with cellular proteins. Here, we discuss in vitro and cell‐based experimental strategies used to identify KDAC‐substrate pairs and evaluate each for the purpose of directly identifying non‐histone substrates of metal‐dependent KDACs. We propose criteria for a combination of reproducible experimental approaches that are necessary to establish a direct enzymatic relationship. This critical analysis of the literature identifies 108 proposed non‐histone substrate‐KDAC pairs for which direct experimental evidence has been reported. Of these, five pairs can be considered well‐established, while another thirteen pairs have both cell‐based and in vitro evidence but lack independent replication and/or sufficient cell‐based evidence. We present a path forward for evaluating the remaining substrate leads and reliably identifying novel KDAC substrates.

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HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth

Cited by 37 publications

References 53 publications

Biological Functions of HMGN Chromosomal Proteins

Biological Functions of HMGN Chromosomal Proteins

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

Critical review of non‐histone human substrates of metal‐dependent lysine deacetylases

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