Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer

Saji, Shigehira; Kawakami, Masayo; Hayashi, Shin Ichi; Yoshida, Nobuyuki; Hirose, Makiko; Horiguchi, Shin Ichiro; Itoh, Akihiro; Funata, Nobuaki; Schreiber, Stuart L.; Yoshida, Minoru; Toi, Masakazu

doi:10.1038/sj.onc.1208646

Cited by 234 publications

(196 citation statements)

References 23 publications

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“…HDAC6 expression is induced by estradiol in MCF7 and other breast cancer cells, and its level of expression correlates with a better prognosis and response to endocrine therapy (19 -21). In addition, patients with ER-positive breast tumors who received tamoxifen as adjuvant therapy for two years have a better prognosis and survival rate when tumors expressed HDAC6 (19). Moreover, inhibition of HDAC6 enhanced heat shock protein 90-mediated maturation of matrix metalloproteinase-2, which was associated with increased breast cancer cell invasion in an in vitro model (34).…”

Section: Discussionmentioning

confidence: 99%

“…However, a portion of HDAC6 can be nuclear in some cells. Notably, experiments performed in breast cancer cells have revealed that HDAC6 is an estrogen target gene (19) and that HDAC6 protein is present in the nuclei of normal breast epithelial cells but is cytoplasmic in adjacent malignant cells (20,21). Moreover, these studies found that HDAC6 expression levels correlate with better prognosis and response to endocrine therapy in breast cancer (19 -21).…”

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confidence: 99%

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Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR

Palijan

Fernandes

Bastien

et al. 2009

Journal of Biological Chemistry

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Ligand-dependent corepressor LCoR was identified as a protein that interacts with the estrogen receptor ␣ (ER␣) ligand binding domain in a hormone-dependent manner. LCoR also interacts directly with histone deacetylase 3 (HDAC3) and HDAC6. Notably, HDAC6 has emerged as a marker of breast cancer prognosis. However, although HDAC3 is nuclear, HDAC6 is cytoplasmic in many cells. We found that HDAC6 is partially nuclear in estrogen-responsive MCF7 cells, colocalizes with LCoR, represses transactivation of estrogen-inducible reporter genes, and augments corepression by LCoR. In contrast, no repression was observed upon HDAC6 expression in COS7 cells, where it is exclusively cytoplasmic. LCoR binds to HDAC6 in vitro via a central domain, and repression by LCoR mutants lacking this domain was attenuated. Kinetic chromatin immunoprecipitation assays revealed hormone-dependent recruitment of LCoR to promoters of ER␣-induced target genes in synchrony with ER␣. HDAC6 was also recruited to these promoters, and repeat chromatin immunoprecipitation experiments confirmed the corecruitment of LCoR with ER␣ and with HDAC6. Remarkably, however, although we find evidence for corecruitment of LCoR and ER␣ on genes repressed by the receptor, LCoR and HDAC6 failed to coimmunoprecipitate, suggesting that they are part of distinct complexes on these genes. Although small interfering RNA-mediated knockdown of LCoR or HDAC6 augmented expression of an estrogen-sensitive reporter gene in MCF7 cells, unexpectedly their ablation led to reduced expression of some endogenous estrogen target genes. Taken together, these data establish that HDAC6 can function as a cofactor of LCoR but suggest that they may act in enhance expressing some target genes.Nuclear receptors are ligand-regulated transcription factors whose activities are controlled by a variety of lipophilic extracellular signals, including steroid and thyroid hormones, metabolites of vitamins A (retinoids) and D (1, 2). DNA-bound nuclear receptors regulate transcription by recruiting complexes of coregulatory proteins, classified as coactivators or corepressors depending on whether they act to stimulate or repress transcription (2-4). Many coactivators interact with receptors through signature LXXLL motifs, known as NR boxes, which are oriented within a hydrophobic pocket of agonist-bound receptor ligand binding domains (5). Several coactivators or their associated cofactors possess histone acetyltransferase activity, which essentially caps positively charged lysine residues and loosens their association with DNA, facilitating chromatin remodeling and subsequent access of the transcriptional machinery to promoters.Nuclear receptor corepressors NCoR 7 and SMRT were isolated as factors that interacted with hormone-free but not hormone-bound thyroid and retinoid receptors (6, 7). They bind to receptor ligand binding domains through extended LXXX-IXXX(L/I) motifs known as CoRNR boxes (8, 9) and recruit multiprotein complexes implicated in transcriptional repression and histone deacetylatio...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR

Palijan

Fernandes

Bastien

et al. 2009

Journal of Biological Chemistry

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“…Depending on the type of cancer, the HDAC6 expression level could be considered either as a good prognosis indicator (Zhang et al, 2004) or, in contrast, as a predictor of poor prognosis and tumor aggressiveness (Osada et al, 2004;Hayashi and Yamaguchi, 2006;Sakuma et al, 2006). Indeed, HDAC6 detection has been reported to correlate with survival in a subset of tamoxifen-treated ER-positive breast cancer patients (Saji et al, 2005). Another report identified positive HDAC6 staining with decreased survival in ER-positive breast cancer patients, using HDAC6 as a prototypical estrogen-regulated gene (Yoshida et al, 2004).…”

Section: Hdac6: a Therapeutic Target?mentioning

confidence: 99%

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

et al. 2007

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Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin-binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli.

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“…Multiple HDAC enzymes have been identified, of which HDAC1 to HDAC10 are expressed in malignant cells (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). To understand the spectrum of HDACs inhibited by droxinostat and determine whether selective HDAC inhibition is sufficient to sensitize cells to FAS and TRAIL, we examined the spectrum of HDAC enzymes inhibited by droxinostat.…”

Section: Droxinostat Selectively Inhibits Hdac3 Hdac6 and Hdac8mentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Wood

Dalili

Simpson

et al. 2010

Molecular Cancer Therapeutics

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Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246-56. ©2010 AACR.

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Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer

Cited by 234 publications

References 23 publications

Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR

Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

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