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Cancers
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Targeting Histone Deacetylases in Cancer
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Targeting Histone Deacetylases in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 33686

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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The processes of human cancer initiation, progression, and metastasis are essentially linked to pathologic epigenetic deregulations via DNA methylation and/or histone modification.

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

To date, most chemically developed histone deacetylase inhibitors (HDACis) have not been HDAC class or HDAC class member-specific. Therefore, the development of new highly selective histone deacetylase inhibitors is a challenging and very promising scientific field. Additionally, treatment strategies combining HDACis with approved anticancer drugs could essentially improve the therapeutic success rate through inhibition of the tumor resistance mechanism or re-induction of primarily epigenetic silenced and consecutive possible druggable proteins in future.

This Special Issue calls for the contribution of original research papers and reviews focused on targeting histone deacetylases in human cancer and their 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.

Assoc. Prof. Dr. Daniel Neureiter
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Epigenetic dependent carcinogenesis
  • Histone modulation
  • Histone deacetylases (HDACs)
  • HDAC profiling in human cancer
  • HDAC inhibitor (HDACi) development and mechanism in human cancer
  • Combinatory treatment strategies of HDACis
  • HDACis inhibition of cancer therapy resistance mechanism
  • HDACis induction of epigenetic silenced druggable proteins
  • Clinical role of HDACis in human cancer

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Published Papers (6 papers)

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Editorial

Jump to: Research, Review

5 pages, 616 KiB  
Editorial
Can We Efficiently Target HDAC in Cancer?
by Tobias Kiesslich and Daniel Neureiter
Cancers 2022, 14(16), 4058; https://doi.org/10.3390/cancers14164058 - 22 Aug 2022
Cited by 4 | Viewed by 1596
Abstract
According to the hallmarks of cancer, typical processes of human cancer initiation, progression, and metastasis are essentially influenced by pathologic epigenetic deregulations via DNA methylation and/or histone modification [...] Full article
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
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Research

Jump to: Editorial, Review

20 pages, 5958 KiB  
Article
HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer
by Christian Mayr, Tobias Kiesslich, Sara Erber, Dino Bekric, Heidemarie Dobias, Marlena Beyreis, Markus Ritter, Tarkan Jäger, Bettina Neumayer, Paul Winkelmann, Eckhard Klieser and Daniel Neureiter
Cancers 2021, 13(15), 3862; https://doi.org/10.3390/cancers13153862 - 31 Jul 2021
Cited by 19 | Viewed by 3493
Abstract
Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell [...] Read more.
Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines. The screening results indicate a heterogeneous expression of HDACs across the studied cell lines. We next tested the effect of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect (i) is dose- and cell-line-dependent, (ii) does not correlate with HDAC isoform expression, and (iii) is most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses demonstrated that romidepsin induces apoptosis in BTC cells, reduces HDAC activity, and increases acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. In conclusion, HDAC class I inhibition in BTC cells by romidepsin is highly effective in vitro and encourages further in vivo evaluation in BTC. In situ assessment of HDAC 2 expression in BTC specimens indicates its importance for oncogenesis and/or progression of BTC as well as for the prognosis of BTC patients. Full article
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
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35 pages, 5087 KiB  
Article
Proteomic Studies of Primary Acute Myeloid Leukemia Cells Derived from Patients Before and during Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid and Valproic Acid
by Maria Hernandez-Valladares, Rebecca Wangen, Elise Aasebø, Håkon Reikvam, Frode S. Berven, Frode Selheim and Øystein Bruserud
Cancers 2021, 13(9), 2143; https://doi.org/10.3390/cancers13092143 - 29 Apr 2021
Cited by 8 | Viewed by 5551
Abstract
All-trans retinoic acid (ATRA) and valproic acid (VP) have been tried in the treatment of non-promyelocytic variants of acute myeloid leukemia (AML). Non-randomized studies suggest that the two drugs can stabilize AML and improve normal peripheral blood cell counts. In this context, we [...] Read more.
All-trans retinoic acid (ATRA) and valproic acid (VP) have been tried in the treatment of non-promyelocytic variants of acute myeloid leukemia (AML). Non-randomized studies suggest that the two drugs can stabilize AML and improve normal peripheral blood cell counts. In this context, we used a proteomic/phosphoproteomic strategy to investigate the in vivo effects of ATRA/VP on human AML cells. Before starting the combined treatment, AML responders showed increased levels of several proteins, especially those involved in neutrophil degranulation/differentiation, M phase regulation and the interconversion of nucleotide di- and triphosphates (i.e., DNA synthesis and binding). Several among the differentially regulated phosphorylation sites reflected differences in the regulation of RNA metabolism and apoptotic events at the same time point. These effects were mainly caused by increased cyclin dependent kinase 1 and 2 (CDK1/2), LIM domain kinase 1 and 2 (LIMK1/2), mitogen-activated protein kinase 7 (MAPK7) and protein kinase C delta (PRKCD) activity in responder cells. An extensive effect of in vivo treatment with ATRA/VP was the altered level and phosphorylation of proteins involved in the regulation of transcription/translation/RNA metabolism, especially in non-responders, but the regulation of cell metabolism, immune system and cytoskeletal functions were also affected. Our analysis of serial samples during the first week of treatment suggest that proteomic and phosphoproteomic profiling can be used for the early identification of responders to ATRA/VP-based treatment. Full article
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
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Graphical abstract

21 pages, 22292 KiB  
Article
Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma
by Sanne Venneker, Alwine B. Kruisselbrink, Zuzanna Baranski, Ieva Palubeckaite, Inge H. Briaire-de Bruijn, Jan Oosting, Pim J. French, Erik H. J. Danen and Judith V. M. G. Bovée
Cancers 2020, 12(12), 3589; https://doi.org/10.3390/cancers12123589 - 30 Nov 2020
Cited by 20 | Viewed by 2840
Abstract
Mutations in the isocitrate dehydrogenase (IDH1 or IDH2) genes are common in enchondromas and chondrosarcomas, and lead to elevated levels of the oncometabolite D-2-hydroxyglutarate causing widespread changes in the epigenetic landscape of these tumors. With the use of a DNA methylation [...] Read more.
Mutations in the isocitrate dehydrogenase (IDH1 or IDH2) genes are common in enchondromas and chondrosarcomas, and lead to elevated levels of the oncometabolite D-2-hydroxyglutarate causing widespread changes in the epigenetic landscape of these tumors. With the use of a DNA methylation array, we explored whether the methylome is altered upon progression from IDH mutant enchondroma towards high-grade chondrosarcoma. High-grade tumors show an overall increase in the number of highly methylated genes, indicating that remodeling of the methylome is associated with tumor progression. Therefore, an epigenetics compound screen was performed in five chondrosarcoma cell lines to therapeutically explore these underlying epigenetic vulnerabilities. Chondrosarcomas demonstrated high sensitivity to histone deacetylase (HDAC) inhibition in both 2D and 3D in vitro models, independent of the IDH mutation status or the chondrosarcoma subtype. siRNA knockdown and RNA expression data showed that chondrosarcomas rely on the expression of multiple HDACs, especially class I subtypes. Furthermore, class I HDAC inhibition sensitized chondrosarcoma to glutaminolysis and Bcl-2 family member inhibitors, suggesting that HDACs define the metabolic state and apoptotic threshold in chondrosarcoma. Taken together, HDAC inhibition may represent a promising targeted therapeutic strategy for chondrosarcoma patients, either as monotherapy or as part of combination treatment regimens. Full article
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
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Review

Jump to: Editorial, Research

43 pages, 2734 KiB  
Review
Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives
by Robert Jenke, Nina Reßing, Finn K. Hansen, Achim Aigner and Thomas Büch
Cancers 2021, 13(4), 634; https://doi.org/10.3390/cancers13040634 - 5 Feb 2021
Cited by 102 | Viewed by 10159
Abstract
The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, [...] Read more.
The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs). Full article
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
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31 pages, 2682 KiB  
Review
HDAC6—An Emerging Target Against Chronic Myeloid Leukemia?
by Hélène Losson, Michael Schnekenburger, Mario Dicato and Marc Diederich
Cancers 2020, 12(2), 318; https://doi.org/10.3390/cancers12020318 - 29 Jan 2020
Cited by 17 | Viewed by 8995
Abstract
Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors [...] Read more.
Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML. Full article
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
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