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Roles of HDACs and HDAC Inhibitors in Human Cancers
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Roles of HDACs and HDAC Inhibitors in Human Cancers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 30873

Special Issue Editor

Dr. Daniel Neureiter

E-Mail Website
Guest Editor
Uniklinikum Salzburg, Landeskrankenhaus, Universitätsinstitut für Pathologie der PMU, Cancer Cluster Salzburg, 5020 Salzburg, Austria
Interests: cancerogenesis; epigenetics; histone deacetylases; miRNA; gastrointestinal tract; hepatopancreatic cancer; epithelial-mesen-chymal-transition; targeted therapy; tumor regression; inflammation
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Special Issue Information

Dear Colleagues,

Pathologic alterations in epigenetic regulation of gene function have been found to be essentially involved in cancer initiation, progression and metastasis. On molecular and cellular levels, aberrantly active epigenetic factors cause altered gene expression patterns especially linked to epithelial to mesenchymal transition (EMT) and chemo-resistance.

Modifications of histones such as histone de-/acetylation represent a major epigenetic regulatory mechanism and play a significant role in human cancerogenesis. Histone deacetylation processes are regulated by a group of enzymes called histone deacetylases (HDACs), categorized in four classes. Overexpression of HDACs has been reported in several human cancer types, making these enzymes an interesting new potential therapeutic target. HDACs do also regulate the acetylation status of a variety of other non-histone substrates, including key tumour oncogenetic and suppressive genes as wells as associated proteins.

Specific inhibition of HDACs promotes tumour cells to undergo apoptosis, and cell-based in vitro as well as in vivo studies have shown a number of other outcomes to result from Histone deactelyase inhibitor (HDI) treatment, including cell-cycle arrest, cell differentiation, anti-angiogenesis and autophagy. Therefore, HDIs represent a promising class of drugs with therapeutic implications in tumour research.

To date, four HDIs have already been approved as anticancer agents: Belinostat, panobinostat, romidepsin and vorinostat. Nevertheless, there is strong interest in increasing the understanding of the pharmacology and underlying mechanisms of action as well as the specific targets of HDIs. This will be helpful for optimizing these drugs and for the development of more agents, which specifically target malfunctioning HDACs. Other than that the detection of biomarkers to predict HDI treatment responsiveness is also a critical issue regarding this topic.

This Special Issue calls for the contribution of original research papers and reviews focusing on HDACs and the role of HDAC inhibition in human cancer therapies to provide both, an up-to-date overview of the current knowledge as well as a platform to present novel scientific results addressing the promising increasingly cited research field of epigenetics in cancer therapy.

Dr. Daniel Neureiter
Guest Editor

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Keywords

  • Epigenetic dependent cancerogenesis
  • Histone modulation
  • Histone deacetylases (HDACs)
  • HDAC profiling in human cancer
  • HDAC linked epithelial-mesenchymal-transition and chemoresistance mechanism in human cancer
  • HDAC inhibitor (HDACi) development and mechanism in human cancer
  • Combinatory treatment strategies of HDACis
  • Clinical role of HDACis in human cancer

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Published Papers (5 papers)

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Research

16 pages, 4236 KiB  
Article
HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells
by Shu-Huey Chen, Jyh-Ming Chow, Yao-Yu Hsieh, Chun-Yu Lin, Kai-Wen Hsu, Wen-Shyang Hsieh, Wei-Ming Chi, Beished M. Shabangu and Chia-Hwa Lee
Int. J. Mol. Sci. 2019, 20(9), 2271; https://doi.org/10.3390/ijms20092271 - 8 May 2019
Cited by 24 | Viewed by 5530
Abstract
Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%–20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated [...] Read more.
Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%–20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase and eventually to a blast crisis, limiting treatment options and resulting in a poor survival rate. Thus, we investigated whether histone deacetylase inhibitors (HDACis) could be used as a potential anticancer therapy for imatinib-resistant CML (IR-CML) patients. By applying a noninvasive apoptosis detection sensor (NIADS), we found that panobinostat significantly enhanced cell apoptosis in K562 cells. A further investigation showed that panobinostat induced apoptosis in both K562 and imatinib-resistant K562 (IR-K562) cells mainly via H3 and H4 histone acetylation, whereas panobinostat targeted cancer stem cells (CSCs) in IR-K562 cells. Using CRISPR/Cas9 genomic editing, we found that HDAC1 and HDAC2 knockout cells significantly induced cell apoptosis, indicating that the regulation of HDAC1 and HDAC2 is extremely important in maintaining K562 cell survival. All information in this study indicates that regulating HDAC activity provides therapeutic benefits against CML and IR-CML in the clinic. Full article
(This article belongs to the Special Issue Roles of HDACs and HDAC Inhibitors in Human Cancers)
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13 pages, 3795 KiB  
Article
HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
by Ching-Ling Lin, Ming-Lin Tsai, Chun-Yu Lin, Kai-Wen Hsu, Wen-Shyang Hsieh, Wei-Ming Chi, Li-Chi Huang and Chia-Hwa Lee
Int. J. Mol. Sci. 2019, 20(2), 454; https://doi.org/10.3390/ijms20020454 - 21 Jan 2019
Cited by 41 | Viewed by 6858
Abstract
Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. [...] Read more.
Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. The clinical management of both ATC and STC is very similar because they are not particularly responsive to radiotherapy and chemotherapy. This inspired us to explore a novel and effective clinically approved therapy for ATC treatment. Histone deacetylase inhibitor (HDACi) drugs are recently FDA-approved drug for malignancies, especially for blood cell cancers. Therefore, we investigated whether an HDACi drug acts as an effective anticancer drug for advanced thyroid cancers. Cell viability analysis of panobinostat treatment demonstrated a significant IC50 of 0.075 µM on SW579 STC cells. In addition, panobinostat exposure activated histone acetylation and triggered cell death mainly through cell cycle arrest and apoptosis-related protein activation. Using CRISPR/Cas9 to knock out HDAC1 and HDAC2 genes in SW579 cells, we observed that the histone acetylation level and cell cycle arrest were enhanced without any impact on cell growth. Furthermore, HDAC1 and HDAC2 double knockout (KO) cells showed dramatic cell apoptosis activation compared to HDAC1 and HDAC2 individual KO cells. This suggests expressional and biofunctional compensation between HDAC1 and HDAC2 on SW579 cells. This study provides strong evidence that panobinostat can potentially be used in the clinic of advanced thyroid cancer patients. Full article
(This article belongs to the Special Issue Roles of HDACs and HDAC Inhibitors in Human Cancers)
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26 pages, 5305 KiB  
Article
Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure–Activity Relations of New Inhibitors of HDAC and/or Tubulin Function
by Florian Schmitt, Lisa Chiara Gosch, Alexandra Dittmer, Matthias Rothemund, Thomas Mueller, Rainer Schobert, Bernhard Biersack, Andrea Volkamer and Michael Höpfner
Int. J. Mol. Sci. 2019, 20(2), 383; https://doi.org/10.3390/ijms20020383 - 17 Jan 2019
Cited by 23 | Viewed by 7091
Abstract
New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps. While their antiproliferative and microtubule disrupting effect was most pronounced for derivatives with short spacers, [...] Read more.
New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps. While their antiproliferative and microtubule disrupting effect was most pronounced for derivatives with short spacers, HDAC inhibition was strongest for those with longer spacers. These findings were further supported by computational methods such as structure-based docking experiments exploring the target interactions of the derivatives with varying linkers. For instance, compounds featuring short four-atom spacers between cap and hydroxamic acid inhibited the growth of various cancer cell lines and human endothelial hybrid cells with IC50 values in the low nanomolar range. In line with their ability to inhibit the microtubule assembly, four- and five-atom spacered hydroxamic acids caused an accumulation of 518A2 melanoma cells in G2/M phase, whereas a compound featuring a six-atom spacer and performing best in HDAC inhibition, induced a G1 arrest in these cells. All these beneficial anticancer activities together with their selectivity for cancer cells over non-malignant cells, point out the great potential of these novel pleiotropic HDAC and tubulin inhibitors as drug candidates for cancer therapy. Full article
(This article belongs to the Special Issue Roles of HDACs and HDAC Inhibitors in Human Cancers)
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16 pages, 3046 KiB  
Article
Efficacy of Azatyrosine-Phenylbutyric Hydroxamides, a Histone Deacetylase Inhibitor, on Chemotherapy-Induced Gastrointestinal Mucositis
by Po-Lin Liao, Shih-Hsuan Huang, Chien-Hung Hung, Wei-Kuang Huang, Chi-Hao Tsai, Jaw-Jou Kang, Hui-Po Wang and Yu-Wen Cheng
Int. J. Mol. Sci. 2019, 20(2), 249; https://doi.org/10.3390/ijms20020249 - 10 Jan 2019
Cited by 3 | Viewed by 4150
Abstract
Gastrointestinal mucositis is a serious side effect of chemotherapy. Currently, no effective treatment exists for chemotherapy-induced mucositis, prompting the need to develop an anti-mucositis agent for use in clinics. The present study investigated whether azatyrosine-PBHA (AzP), a histone deacetylase inhibitor, has a therapeutic [...] Read more.
Gastrointestinal mucositis is a serious side effect of chemotherapy. Currently, no effective treatment exists for chemotherapy-induced mucositis, prompting the need to develop an anti-mucositis agent for use in clinics. The present study investigated whether azatyrosine-PBHA (AzP), a histone deacetylase inhibitor, has a therapeutic effect on intestinal mucosa. The results indicated that AzP did not affect the proliferation and viability of cancer cells, outcomes that are achieved by suberoylanilide hydroxamic acid (SAHA). However, AzP could decrease production of the inflammatory mediators interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor-necrosis factor-α (TNF-α). In vivo histopathological assessment showed that AzP reduced cisplatin-induced injury to the jejunum villi and triggered weight loss in the C57BL/6 mice. Immunohistochemistry (IHC) results demonstrated that mice treated with AzP also recovered from cisplatin-induced injury to the intestinal mucosa. Mechanistic in vitro study using DAVID/KEGG enrichment analysis of microarray data and confirmation by a Western blot indicated the influence of AzP on the MEK/ERK and AKT-dependent pathway. In conclusion, the study demonstrated that AzP might regulate the MEK/ERK MAPK signaling pathway to attenuate MCP-1, TNF-α, and IL-6 production and provide opportunities for the development of new anti-inflammatory drugs targeting mucositis. Full article
(This article belongs to the Special Issue Roles of HDACs and HDAC Inhibitors in Human Cancers)
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14 pages, 4202 KiB  
Article
Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells
by Julia Wanek, Martin Gaisberger, Marlena Beyreis, Christian Mayr, Katharina Helm, Florian Primavesi, Tarkan Jäger, Pietro Di Fazio, Martin Jakab, Andrej Wagner, Daniel Neureiter and Tobias Kiesslich
Int. J. Mol. Sci. 2018, 19(10), 3128; https://doi.org/10.3390/ijms19103128 - 12 Oct 2018
Cited by 39 | Viewed by 6457
Abstract
Histone deacetylases (HDACs) play a key role in epigenetic mechanisms in health and disease and their dysfunction is implied in several cancer entities. Analysis of expression patterns in pancreatic neuroendocrine tumors (pNETs) indicated HDAC5 to be a potential target for future therapies. As [...] Read more.
Histone deacetylases (HDACs) play a key role in epigenetic mechanisms in health and disease and their dysfunction is implied in several cancer entities. Analysis of expression patterns in pancreatic neuroendocrine tumors (pNETs) indicated HDAC5 to be a potential target for future therapies. As a first step towards a possible treatment, the aim of this study was to evaluate the in vitro cellular and molecular effects of HDAC5 inhibition in pNET cells. Two pNET cell lines, BON-1 and QGP-1, were incubated with different concentrations of the selective class IIA HDAC inhibitor, LMK-235. Effects on cell viability were determined using the resazurin-assay, the caspase-assay, and Annexin-V staining. Western Blot and immunofluorescence microscopy were performed to assess the effects on HDAC5 functionality. LMK-235 lowered overall cell viability by inducing apoptosis in a dose- and time-dependent manner. Furthermore, acetylation of histone-H3 increased with higher LMK-235 concentrations, indicating functional inhibition of HDAC4/5. Immunocytochemical analysis showed that proliferative activity (phosphohistone H3 and Ki-67) decreased at highest concentrations of LMK-235 while chromogranin and somatostatin receptor 2 (SSTR2) expression increased in a dose-dependent manner. HDAC5 expression was found to be largely unaffected by LMK-235. These findings indicate LMK-235 to be a potential therapeutic approach for the development of an effective and selective pNET treatment. Full article
(This article belongs to the Special Issue Roles of HDACs and HDAC Inhibitors in Human Cancers)
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