The role of histone demethylases in cancer therapy

Hoffmann, Inga; Roatsch, Martin; Schmitt, Martin; Carlino, Luca; Pippel, Martin; Sippl, Wolfgang; Jung, Manfred

doi:10.1016/j.molonc.2012.07.004

Cited by 94 publications

(86 citation statements)

References 148 publications

(239 reference statements)

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“…Nevertheless an epigenetic therapy against cancer is still subject of intense research. A new impetus in this field was given by the discovery of the demethylases [98,99] and the synthesis of their specific inhibitors [100]. A more niche-research concerns class IIa HDACs and their selective inhibitors, which are hypothesized to be less powerful than panHDACis but more specific.…”

Section: Discussionmentioning

confidence: 99%

Selective class IIa HDAC inhibitors: myth or reality

Giorgio

Gagliostro

Brancolini

2014

Cell. Mol. Life Sci.

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The prospect of intervening, through the use of a specific molecule, with a cellular alteration responsible for a disease, is a fundamental ambition of biomedical science. Epigenetic-based therapies appear as a remarkable opportunity to impact on several disorders, including cancer. Many efforts have been made to develop small molecules acting as inhibitors of histone deacetylases (HDACs). These enzymes are key targets to reset altered genetic programs and thus to restore normal cellular activities, including drug responsiveness. Several classes of HDAC inhibitors (HDACis) have been generated, characterized and, in certain cases, approved for the use in clinic. A new frontier is the generation of subtype-specific inhibitors, to increase selectivity and to manage general toxicity. Here we will discuss about a set of molecules, which can interfere with the activity of a specific subclass of HDACs: the class IIa.

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Section: Discussionmentioning

confidence: 99%

Selective class IIa HDAC inhibitors: myth or reality

Giorgio

Gagliostro

Brancolini

2014

Cell. Mol. Life Sci.

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“…This has been described in several reviews, (15,16,24) and we will therefore limit the discussion here to some key examples. Table 1 provides an overview for KDMs and their association with human cancer.…”

Section: Kdms In Cancermentioning

confidence: 99%

Roles of histone methyl‐modifying enzymes in development and progression of cancer

et al. 2013

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Retroviral insertional mutagenesis in mice is considered a powerful forward genetic strategy to identify disease genes involved in cancer. Our high-throughput screens led to frequent identification of the genes encoding the enzymes engaged in histone lysine methylation. Histone methylation can positively or negatively impact on gene transcription, and then fulfill important roles in developmental control and cell-fate decisions. A tremendous amount of progress has accelerated the characterization of histone methylations and the enzymes that regulate them. Deregulation of these histone methyl-modifying enzymes has been increasingly recognized as a hallmark of cancer in the last few years. However, in most cases, we have only limited understanding for the molecular mechanisms by which these enzymes contribute to cancer development and progression. In this review, we summarize the current knowledge regarding some of the best-validated examples of histone lysine methyltransferases and demethylases associated with oncogenesis and discuss their potential mechanisms of action. (Cancer Sci 2013; 104: 795-800) A great body of evidence supports that epigenetic changes are responsible for cancer development.(1,2) There are different types of mechanisms in the field of epigenetics: DNA methylation, post-translational modifications of histones, chromatin remodeling and noncoding RNAs. The earliest demonstration of an epigenetic link to cancer was derived from the studies about DNA methylation. Evidence showing the role of DNA hyper-or hypo-methylation in oncogenesis has been accumulating for more than 20 years. However, the role of the other mechanisms is an emerging area of interest. During the past decade, the focus has shifted to studies of post-translational modifications of histones, because alterations in the balance of histone modifications lead to deregulated gene expression and are associated with cancer. The nucleosome, the basic building block of chromatin, is composed of two copies of each histone: H2A, H2B, H3, and H4. The amino-terminal tails of histones are subject to posttranslational modifications (Fig. 1a), which include acetylation, methylation, phosphorylation, ubiquitylation and SUMOylation. These modifications influence the structure of chromatin and show different functional outputs depending on the type, the site and the degree of modifications. The modification pattern of histone has been linked to gene function during development and tumorigenesis.Identification of genes involved in cancer gives us crucial information about the molecular mechanism of cancer development. Genetic screens for mutations contributing to tumor formation in model organisms facilitate the efficient identification of cancer genes in an in vivo setting. Retroviral insertional mutagenesis in mice is one of the potent cancer gene discovery tools.(3) Previously we have accomplished high-throughput cloning of retroviral integration sites from the tumors of murine leukemia virus (MuLV)-infected mice.(4) This led to the identifi...

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“…They can be removed by histone lysine demethylases (KDMs), such as LSD-1 and -2, or JmJDdomain-containing histone demethylases. 13,14 LSD1 demethylates mono-and di-methylated lysines 4 and 9 of histone H3. It is frequently overexpressed in NSCLC and promotes proliferation and invasion.…”

Section: Histone Modifications: Enzymes and Their Inhibitorsmentioning

confidence: 99%

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

et al. 2016

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Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.

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The role of histone demethylases in cancer therapy

Cited by 94 publications

References 148 publications

Selective class IIa HDAC inhibitors: myth or reality

Selective class IIa HDAC inhibitors: myth or reality

Roles of histone methyl‐modifying enzymes in development and progression of cancer

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

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