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HDAC
HDAC HDAC(7)

Histone deacetylases (HDACs), or lysine deacetylases (KDACs), remove acetyl groups from a-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone acetyltransferase. HDAC proteins occur in four groups based on function and DNA sequence similarity. The first two groups are considered classical HDACs whose activities are inhibited by trichostatin A (TSA), whereas the third group is a family of NAD+-dependent proteins not affected by TSA. The fourth group is considered an atypical category of its own, based solely on DNA sequence similarity to the others. Histone tails are normally positively charged due to amine groups present on their lysine and arginine amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amides and decreases the ability of the histones to bind to DNA. This decreased binding allows chromatin expansion, permitting genetic transcription to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription.(1)
HDACs are being found to interact with a variety of non-histone proteins, including transcription factors and co-regulators: Histone deacetylase 6 (HDAC 6), a member of the HDAC family whose major substrate is a-tubulin, has become a target for drug development to treat cancer. HDAC6 is required for the activation of heat-shock factor 1 (HSF1), an activator of heat-shock protein encoding genes (HSPs) and CYLD, a cylindromatosis tumor suppressor gene. HDAC6 contributes to cancer metastasis since its upregulation increases cell motility in breast cancer MCF-7 cells and its interaction with cortactin regulates motility.(5)
High levels of HDAC6 expression were found to correlate with tumorigenesis, and ER positive breast cancer patients who received adjuvant treat ment with TAM showed better survival prognosis. Thus, HDAC6 could potentially be used as an additional marker for prognosis.(5) HDACs are up-regulated in response to hypoxia mediating increased HIF-1a signaling.(6)

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References

1. HDAC. [cited]; Available from: http://en.wikipedia.org/wiki/HDAC.

2. Ikenoue T IK, Zhao B, Guan KL. PTEN acetylation modulates its interaction with PDZ domain. Cancer Res. 2008;68(17):6908-12. PMCID: 18757404.

3. Yao XH NB. Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring. Am J Physiol Regul Integr Comp Physiol. 2008;294(6):R1797-806. PMCID: 18385463.

4. PO H. Ubiquitination, phosphorylation, and acetylation--triple threat in muscle wasting. J Cell Physiol. 2007;213(3):679-89. PMCID: 17657723.

5. Aldana-Masangkay GI SK. The role of HDAC6 in cancer. J Biomed Biotechnol. 2011;2011:875824. PMCID: 21076528.

6. Ellis L HH, Pili R. Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett. 2009;280(2):145-53. PMCID: 19111391.

7. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Reviews Drug Discovery.1:287-99



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Wednesday, September 14, 2016 5:53 PM|Junjiang Fu, Lianmei Zhang, Tao He, Xiuli Xiao, Xiaoyan Liu, Li Wang, Luquan Yang, Manman Yang, Tiandan Zhang, Rui Chen, Jianming Xu|International Journal of Biological Sciences|Labels: HDAC, breast cancer

Loss of estrogen receptor α (ERα) expression and gain of TWIST (TWIST1) expression in breast tumors correlate with increased disease recurrence and metastasis and poor disease-free survival. However, the molecular and functional regulatory relationship between TWIST and ERα are unclear. In this study, we found TWIST was associated with a chromatin region in intron 7 of the human ESR1 gene coding for ERα. This association of TWIST efficiently recruited the nucleosome remodeling and deacetylase (NuRD) repressor complex to this region, which subsequently decreased histone H3K9 acetylation, increased histone H3K9 methylation and repressed ESR1 expression in breast cancer cells. In agreement with these molecular events, TWIST expression was inversely correlated with ERα expression in both breast cancer cell lines and human breast ductal carcinomas. Forced expression of TWIST in TWIST-negative and ERα-positive breast cancer cells such as T47D and MCF-7 cells reduced ERα expression, while knockdown of TWIST in TWIST-positive and ERα-negative breast cancer cells such as MDA-MB-435 and 4T1 cells increased ERα expression. Furthermore, inhibition of histone deacetylase (HDAC) activity including the one in NuRD complex significantly increased ERα expression in MDA-MB-435 and 4T1 cells. HDAC inhibition together with TWIST knockdown did not further increase ERα expression in 4T1 and MDA-MB-435 cells. These results demonstrate that TWIST/NuRD represses ERα expression in breast cancer cells. Therefore, TWIST may serve as a potential molecular target for converting ERα-negative breast cancers to ERα-positive breast cancers, allowing these cancers to restore their sensitivity to endocrine therapy with selective ERα antagonists such as tamoxifen and raloxifene.

Tuesday, September 13, 2016 8:19 PM|Darina L Lazarova, Christopher Chiaro, Terrence Wong, Eric Drago, Anthony Rainey, Shannon O'Malley, Michael Bordonaro|Journal of Cancer|Labels: HDAC, WNT, CRC

Mutations in the WNT/beta-catenin pathway are responsible for initiating the majority of colorectal cancers (CRCs). We have previously shown that hyperactivation of this signaling by histone deacetylase inhibitors (HDACis) such as butyrate, a fermentation product of dietary fiber, promotes CRC cell apoptosis. The extent of association between beta-catenin and the transcriptional coactivator CREB-binding protein (CBP) influences WNT/catenin signaling and, therefore, colonic cell physiology. CBP functions as a histone acetylase (HAT); therefore, we hypothesized that the modulation of WNT/catenin activity by CBP modifies the ability of the HDACi butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that CBP affects the hyperinduction of WNT activity by butyrate. ICG-001, which specifically blocks association between CBP and beta-catenin, abrogates the butyrate-triggered increase in the number of CRC cells with high levels of WNT/catenin signaling. Combination treatment of CRC cells with ICG-001 and butyrate results in cell type-specific effects on apoptosis. Further, both butyrate and ICG-001 repress CRC cell proliferation, with additive effects in suppressing cell growth. Our study strongly suggests that ICG-001-like agents would be effective against butyrate/HDACi-resistant CRC cells. Therefore, ICG-001-like agents may represent an important therapeutic option for CRCs that exhibit low-fold hyperactivation of WNT activity and apoptosis in the presence of HDACis. The findings generated from this study may lead to approaches that utilize modulation of CBP activity to facilitate CRC therapeutic or chemopreventive strategies.

Tuesday, August 23, 2016 9:25 PM|Yoichi Imai, Yoshiro Maru, Junji Tanaka|Cancer Science|Labels: HDAC, leukemia
Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. In addition, studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors exhibit some efficacy in the treatment of acute myelogenous leukemia (AML) with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription (STAT) signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 (HSP90) due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib. This article is protected by copyright. All rights reserved.
Sunday, August 14, 2016 10:05 PM|Zheng, H., Zhao, W., Yan, C., Watson, C. C., Massengill, M., Xie, M., Massengill, C., Noyes, D. R., Martinez, G. V., Afzal, R., Chen, Z., Ren, X., Antonia, S. J., Haura, E. B., Ruffell, B., Beg, A. A.|Clinical Cancer Research recent issues|Labels: HDAC, PD-1/PD-L1, lung cancer

Purpose: A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ~20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response.

Experimental Design: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms.

Results: We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell–dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells.

Conclusions: These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119–32. ©2016 AACR.

Sunday, June 19, 2016 3:00 PM|Current Pharmaceutical Design|Current Pharmaceutical Design via MedWorm.com|Comments|Labels: HDAC
CONCLUSION: Molecular descriptors derived from 3-D Morse and Radial Distribution Function indices were found to be selective in all the models. These molecular descriptors encode common SAR among Vorinostat derivatives were evaluated for their potent HDAC inhibition activity. PMID: 27339433 [PubMed - as supplied by publisher] (Source: Current Pharmaceutical Design)
Thursday, April 28, 2016 9:59 AM|BAEK, M.-H., PARK, J.-Y., RHIM, C. C., PARK, Y., KIM, K.-R., KIM, J.-H., NAM, J.-H.|Anticancer Research recent issues|Labels: HDAC

Aim: Endometrial stromal sarcoma (ESS) is a rare tumor with limited treatment options. Histone deacetylase (HDAC) is a potential therapeutic target in ESS showing a good rate of response in laboratory studies. In this study we investigated the expression of HDAC enzymes in 41 ESS patients. Materials and Methods: Immunohistochemical expression of HDACs was analyzed by tissue microarrays. Results: Strong positive immunoreactivity was observed in 32 (78.0%), 23 (56.1%), 8 (19.5%), 36 (87.8%), 7 (17.1%), 30 (73.2%), 31 (75.6%), and 33 (80.5%) for HDACs 1-8, respectively. Although not statistically significant, HDAC 1, 4, 6, 7, and 8 exhibited a high frequency of strong immunoreactivity linked to a lower 10-year DFS (100.0% vs. 81.3%, p=0.202; 100.0% vs. 83.3%, p=0.393; 90.9% vs. 83.3%, p=0.579; 90.0% vs. 83.9%; and 100.0% vs. 81.8%, p=0.207; respectively). Conclusion: HDACs 1, 4, 6, 7, and 8, that showed an especially high frequency of strong immunoreactivity, may represent potential therapeutic targets for ESS.

Sunday, February 14, 2016 6:09 AM|Expert Opinion on Investigational Drugs|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: HDAC, lung cancer
This article summarizes the pharmacokinetics, pharmacodynamics, mechanisms of action, safety, tolerability, pre-clinical studies and clinical trials of the HDAC inhibitor entinostat, as a novel promissory agent for the treatment of NSCLC. EXPERT OPINION: The field of targeted therapy has increased in lung cancer. However, even now with the current FDA-approved agents, < 15% of patients benefit from these interventions and we are still far from curing lung cancer. New targets are needed. Either in combination with cytotoxic drugs, epigenetic therapy or other molecular targeted drugs, entinostat represents a new potential agent for the treatment of non-small cell carcinomas. However, the preliminary safety and efficacy results from several clinical trials still need to be validated in...
Sunday, February 14, 2016 6:09 AM|Expert Opinion on Investigational Drugs|MedWorm: Cancer Therapy|Comments|Labels: HDAC, AML, MDS, MM
Authors: Stahl M, Gore SD, Vey N, Prebet T Abstract INTRODUCTION: Epigenetic changes and mutations in epigenetic modifiers characterize and likely drive many cases of acute myeloid leukemia and myelodysplastic syndrome. Development of DNA methyltransferase inhibitors has been most successful in these diseases. While many epigenetic marks are potential targets of cancer therapies, histone deacetylase inhibitors (HDACi) have undergone the most advanced development to date. Area Covered: In this review, the authors describe and discuss the biology and the clinical results of HDAC inhibitors in the settings of myeloid malignancies. Expert opinion: While significant results have been achieved in lymphoma and myeloma, efficacy remains limited in myeloid malignancies for both single agent...

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Friday, February 12, 2016 5:08 PM|Journal of Cancer Research and Clinical Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: HDAC, lung cancer
Conclusion Combining proteasome inhibition with HDAC inhibition enhances ER stress, which may contribute to the synergistic anticancer activity observed in NSCLC cell lines. Further preclinical and clinical studies of CFZ + SAHA in NSCLC are warranted. (Source: Journal of Cancer Research and Clinical Oncology)
Conclusions: The development of a new PARPi combination therapy with panobinostat has immediate prospects for rapid translation to the clinic and great potential for improving clinical outcomes for non-BRCAness, chemoresistant ovarian cancer.Citation Format: Andrew J. Wilson, Jeanette Saskowski, Dineo Khabele. The histone deacetylase inhibitor panobinostat sensitizes cyclin E-amplified ovarian cancer cells to poly ADP ribose polymerase inhibitors via E2F1 downregulation.. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B37. (Source: Cancer Research)

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A major question facing the use of epigenetic therapies in cancer is the specificity in reactivating gene expression. In addition, combined targeting of DNA and histone methylation remains largely unexplored despite the promising synergistic effects observed from combining DNA methyltransferase inhibitors with HDAC inhibitors.To address these questions, we performed RNA-seq in colon cancer (SW48) and breast cancer (MCF7) models treated with a DNA methyltransferase inhibitor (Decitabine/DAC) either alone or in combination with a LSD1 inhibitor (S2101), G9a inhibitor (UNC0638), EZH2 inhibitor (GSK343) or a HDAC inhibitor (Depsipeptide). Additionally, we performed ChIP-seq (H3K4me2, H3K9me2, and H3K27me3) and DNA methylation analysis (DREAM) on SW48 cells. Both low dose (100nM) and intermedia...