ERα and ERβ expression and transcriptional activity are differentially regulated by HDAC inhibitors (original) (raw)
Related papers
Histone deacetylase inhibition and estrogen signalling in human breast cancer cells
Biochemical Pharmacology, 2004
Estrogens are steroid hormones, which act through specific nuclear estrogen receptors (ERa and ERb) and are important regulators of breast cancer growth. These receptors control gene expression by recruiting transcriptional cofactors that exhibit various enzymatic activities such as histone acetyltransferase or histone deacetylase (HDAC) which target histone as well as non-histone substrates. The ERa itself and some of the transcriptional regulators have been shown to be acetylated proteins. Research performed over the last decade has highlighted the role of HDAC inhibitors (HDACi) as modulators of transcriptional activity and as a new class of therapeutic agents. In human cancer cells, inhibition of HDACs controls the expression of the ERa gene and the transcriptional activity in response to partial antiestrogens such as 4-hydroxytamoxifen. Various HDACi strongly inhibit breast cancer cell proliferation and ERa-negative (ERÀ) appear less sensitive than ERa-positive (ERþ) cell lines. p21 WAF1/CIP1 gene expression, in relation with ERa levels, could play a role in this differential response of breast cancer cells to hyperacetylating agents. # 2004 Elsevier Inc. All rights reserved.
Anti-estrogenic actions of histone deacetylase inhibitors in MCF-7 breast cancer cells
Endocrine Related Cancer, 2007
Anti-estrogens are the current endocrine therapy of choice in the treatment of estrogen receptor (ER)-positive breast cancers. Histone deacetylase inhibitors (HDACi) also constitute a promising treatment for therapy, and combination of anti-estrogens with HDACi may improve efficacy while reducing side effects. We have examined the effect of the HDACi sodium butyrate and suberoylanilide hydroxamic acid (SAHA), alone and in combination with 17b-estradiol (E 2) and the pure anti-estrogen ICI 182.780 (ICI) in human MCF-7 breast cancer cells. HDACi caused a sustained increase of histone H3 acetylation and caused cell death as shown by flow cytometry analysis. In surviving cells, both inhibitors were even stronger than ICI in depleting cyclin D1 levels, inducing expression of the cyclin kinase inhibitor p21 Waf1/Cip1 , blocking phosphorylation of the retinoblastoma protein, or inhibiting cell growth. No additive effects of ICI with either butyrate or SAHA were found. In addition, these drugs were able to antagonize the effects of E 2 on expression of cell cycle proteins, cell growth, and transcription of ER-dependent genes. The anti-estrogenic effects of HDACi appear to be related to a strong downregulation of the expression of ERa that appears to be secondary to both transcriptional and post-transcriptional regulation. ERa phosphorylation is involved in estrogen signaling, and HDACi also prevented receptor phosphorylation in Ser-118 both in the absence and presence of ER ligands. These results provide further support for the use of deacetylase inhibitors as chemotherapeutic agents in the treatment of breast cancer tumors.
Journal of Molecular Endocrinology, 2004
In this study, we have analysed the effects of histone deacetylase (HDAC) inhibition on estrogen receptor (ER) expression and on its transcriptional activity in response to antiestrogens. In several breast cancer cell lines, trichostatin A (TSA), a potent HDAC inhibitor, strongly decreases ERalpha expression in a dose-dependent manner. This repression is observed independently of the presence of ligand and also occurs in ovarian and endometrial cell lines. In addition, we show that in MCF7 cells bearing a stably transfected reporter plasmid (MELN cells), partial antiestrogens such as 4-OH-tamoxifen (OHTam), raloxifen or LY117018, switch to an agonist activity upon HDAC inhibition. This effect is blocked by the pure antiestrogen ICI182780 and exhibits a half-maximal concentration of OHTam equivalent to its affinity for ERalpha. The TSA-dependent decrease of ERalpha expression is required to induce the agonist switch of OHTam properties as it is lost in cells constitutively expressing...
Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer
Anticancer Research, 2017
With a lifetime risk estimated to be one in eight in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide. Patients are often treated with anti-estrogens, but it is common that some tumors develop resistance to therapy. The causation and progression of cancer is controlled by epigenetic processes, so there is an ongoing interest in research into mechanisms, genes and signaling pathways associating carcinogenesis with epigenetic modulation of gene expression. Given the fact that histone deacetylases (HDACs) have a great impact on chromatin remodeling and epigenetics, their inhibitors have become a very interesting field of research. Aim: This review focused on the use of HDAC inhibitors as anticancer treatment and explains the mechanisms of therapeutic effects on breast cancer. We anticipate further clinical benefits of this new class of drugs, both as single agents and in combination therapy. Molecules such as suberoylanilide hydroxamic acid, trichostatin A, suberoylbis-hydroxamic acid, panobinostat, entinostat, valproic acid, sodium butyrate, SK7041, FTY720, N-(2-hydroxyphenyl)-2-propylpentanamide, Scriptaid, YCW1, santacruzamate A and ferrocenyl have shown promising antitumor effects against breast cancer. HDAC inhibitors consists an attractive field for targeted therapy against breast cancer. Future therapeutic strategies will include combination of HDAC inhibitors and chemotherapy or other inhibitors, in order to target multiple oncogenic signaling pathways. More trials are needed. Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide. According to the American Cancer Society about 12% U.S. women will develop breast cancer during their lifetime. Moreover, in 2015, about 2,300 men were diagnosed with breast cancer and 440 died from the disease (1, 2). In approximately 90% of breast cancer cases, estrogen receptor α (ERα), progesterone receptor (PR), or the human epidermal growth factor receptor2 (HER2/ERBB2) protooncogenic receptor are expressed. In many of these patients, treatment with anti-estrogens (e.g. aromatase inhibitors, tamoxifen, fulvestrant) and HER2-targeted agents has improved their survival significantly (3, 4). However, despite 35 Τhis article is freely accessible online.
Cancer Biology & Therapy, 2007
Our previous studies demonstrated that inhibition of histone deacetylases (HDACs) by trichostatin A reactivates estrogen receptor alpha (ER) gene expression in ER-negative breast cancer cells. Here, we use the clinically relevant HDAC inhibitor, LBH589 (LBH) to explore the roles of HDAC in ER gene silencing. In the ER-negative human breast cancer lines, MDA-MB-231 and MDA-MB-435, treatment with LBH for 24 hours restored ER mRNA and protein expression without a concomitant demethylation of the CpG island at the ER promoter. The expression of ER mRNA was sustained at least 96 hours after withdrawal of LBH treatment. Restoration of ER expression by LBH enhanced 4-hydroxytamoxifen sensitivity in MDA-MB-231 cells. The molecular mechanisms by which LBH reactivated silenced ER gene in MDA-MB-231 cells were examined with emphasis on chromatin structure reorganization. By chromatin immunoprecipitation analysis, LBH treatment released DNMT1, HDAC1, and the H3 lysine 9 (H3-K9) methyltransferase SUV39H1 from the ER promoter. Such changes were associated with an active chromatin formation manifested as accumulation of acetylated histones H3 and H4, a decrease in methylated H3-K9, and an impaired binding of heterochromatin protein 1 (HP1a) at the promoter. Our findings suggest that HDAC inhibitors could restore expression of the silenced ER gene by reorganizing the heterochromatin-associated proteins without alteration in promoter DNA hypermethylation.
PLOS One, 2012
Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERa and ERb, which elicit opposing roles in regulating proliferation: ERa is proliferative while ERb is anti-proliferative. Exogenous expression of ERb in ERa-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERb might oppose ERa's proliferative effects via formation of ERa/b heterodimers. Despite biochemical and cellular evidence of ERa/b heterodimer formation in cells co-expressing both receptors, the biological roles of the ERa/b heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERa/b heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERa/b heterodimer-selective ligands at defined concentrations, we demonstrate that ERa/b heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERa and ERb in human breast tissue microarrays, we demonstrate that ERa and ERb are co-expressed in the same cells in breast tumors. The co-expression of ERa and ERb in the same cells supports the possibility of ERa/b heterodimer formation at physio-and pathological conditions, further suggesting that targeting ERa/b heterodimers might be a novel therapeutic approach to the treatment of cancers which coexpress ERa and ERb.
PLoS ONE, 2012
Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERa and ERb, which elicit opposing roles in regulating proliferation: ERa is proliferative while ERb is anti-proliferative. Exogenous expression of ERb in ERa-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERb might oppose ERa's proliferative effects via formation of ERa/b heterodimers. Despite biochemical and cellular evidence of ERa/b heterodimer formation in cells co-expressing both receptors, the biological roles of the ERa/b heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERa/b heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERa/b heterodimer-selective ligands at defined concentrations, we demonstrate that ERa/b heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERa and ERb in human breast tissue microarrays, we demonstrate that ERa and ERb are co-expressed in the same cells in breast tumors. The co-expression of ERa and ERb in the same cells supports the possibility of ERa/b heterodimer formation at physio-and pathological conditions, further suggesting that targeting ERa/b heterodimers might be a novel therapeutic approach to the treatment of cancers which coexpress ERa and ERb.
Nature Medicine, 2005
Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer 1-4 . Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.
Cancer research, 2002
We showed previously that prolonged treatment of a MCF-7-derived cell line with hydroxytamoxifen (OHT) induces the irreversible silencing of some estrogen-responsive genes, whereas OHT-resistant cell growth appears simultaneously (E. Badia et al., Cancer Res., 60: 4130-4138, 2000). Based on the hypothesis that particular gene silencings could be involved in triggering the resistance phenomenon, we focused our study on the mechanism of OHT-induced silencing. More precisely, we wished to determine to what extent the recruited histone deacetylase (HDAC) activity, which is known to be involved in the repressive effect induced by antagonist ligands of nuclear receptors, could participate in various aspects of OHT effects, particularly in gene silencing. A fusion protein (HDAC-EG) of human HDAC1 fused with the estrogen receptor DNA-binding domain and the glucocorticoid receptor ligand-binding domain allowed targeting of chimeric HDAC1 activity on estrogen-responsive elements (EREs) in the...