Special Issue "Histone Modification Enzymes and Long Noncoding RNAs in Cancer"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (12 November 2018)

Special Issue Editors

Guest Editor
Prof. Tao Liu

Group Leader - Histone Modification in Cancer, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
Website | E-Mail
Interests: cancer therapy; histone modification enzymes; Histone modification enzyme inhibitors; Long noncoding RNA
Co-Guest Editor
Dr. Jenny Wang

Group Leader - Cancer and Stem Cell Biology Group, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
Website | E-Mail
Interests: Cancer stem cells; signaling pathway; non-coding RNA; epigenetics; cancer metabolism

Special Issue Information

Dear Colleagues,

Post-translational histone modifications are regulated by histone modification enzymes, which can be divided into writers, erasers, and readers. Histone writers include histone acetyltransferases and methyltransferases, while histone deacetylases and demethylases are among erasers. Histone readers, such as BET (bromodomain and extra-terminal domain) protein family and SWI/SNF (switch/sucrose non-fermentable) complex, recognize histone acetylation and methylation. Through modulating gene transcription, histone modification enzymes significantly down-regulate tumor suppressor gene and up-regulate oncogene expression, and thereby play critical roles in tumor initiation and progression. Small molecule inhibitors of the aberrant histone modifications have been developed, and some of them, such as the histone deacetylase inhibitors vorinostat and panobinostat, have been approved for cancer therapy in patients. More recently, histone methyltransferase inhibitors, such as the DOT1L inhibitor EPZ-5676 and the EZH2 inhibitor Tazemetostat, histone demethylase inhibitors, such as the LSD1 inhibitors GSK2879552 and RG6016, and the BET bromodomain inhibitors OTX015 and GSK525762 have entered various phases of clinical trials in cancer patients.

While well-known to form protein complexes with transcriptional activators, repressors, co-activators and co-repressors, histone modification enzymes have recently been demonstrated to be recruited by long noncoding RNAs (lncRNAs) to target gene promoters and enhancers, and lncRNAs are emerging as critical regulators of gene transcription, tumor initiation and progression. Unlike protein-coding genes, the majority of lncRNAs are expressed in tissue, cell lineage and developmental stage-dependent manners. This unique expression pattern makes lncRNAs better cancer biomarkers and ideal therapeutic targets. Development of inhibitors which block the interaction between lncRNAs and their partner histone modification enzymes is likely to provide novel cancer treatments with better therapeutic index.

In this Special Issue, we welcome reviews, new methodologies and original articles covering histone modification enzymes and lncRNAs.

Prof. Tao Liu
Dr. Jenny Wang
Guest Editors

Manuscript Submission Information

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Keywords

  • Histone modification enzymes
  • Histone modification enzyme inhibitors
  • Gene transcription
  • Long noncoding RNA
  • Cancer therapy

Published Papers (4 papers)

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Review

Open AccessReview The Complex Interplay between Metabolic Reprogramming and Epigenetic Alterations in Renal Cell Carcinoma
Received: 1 March 2019 / Revised: 27 March 2019 / Accepted: 28 March 2019 / Published: 2 April 2019
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Abstract
Renal cell carcinoma (RCC) is the most common malignancy affecting the kidney. Current therapies are mostly curative for localized disease, but do not completely preclude recurrence and metastization. Thus, it is imperative to develop new therapeutic strategies based on RCC biological properties. Presently, [...] Read more.
Renal cell carcinoma (RCC) is the most common malignancy affecting the kidney. Current therapies are mostly curative for localized disease, but do not completely preclude recurrence and metastization. Thus, it is imperative to develop new therapeutic strategies based on RCC biological properties. Presently, metabolic reprograming and epigenetic alterations are recognized cancer hallmarks and their interactions are still in its infancy concerning RCC. In this review, we explore RCC biology, highlighting genetic and epigenetic alterations that contribute to metabolic deregulation of tumor cells, including high glycolytic phenotype (Warburg effect). Moreover, we critically discuss available data concerning epigenetic enzymes’ regulation by aberrant metabolite accumulation and their consequences in RCC emergence and progression. Finally, we emphasize the clinical relevance of uncovering novel therapeutic targets based on epigenetic reprograming by metabolic features to improve treatment and survival of RCC patients. Full article
(This article belongs to the Special Issue Histone Modification Enzymes and Long Noncoding RNAs in Cancer)
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Open AccessReview KDM4B: A Nail for Every Hammer?
Received: 21 December 2018 / Revised: 5 February 2019 / Accepted: 7 February 2019 / Published: 12 February 2019
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Abstract
Epigenetic changes are well-established contributors to cancer progression and normal developmental processes. The reversible modification of histones plays a central role in regulating the nuclear processes of gene transcription, DNA replication, and DNA repair. The KDM4 family of Jumonj domain histone demethylases specifically [...] Read more.
Epigenetic changes are well-established contributors to cancer progression and normal developmental processes. The reversible modification of histones plays a central role in regulating the nuclear processes of gene transcription, DNA replication, and DNA repair. The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia. In this review, we discuss what is known about the regulation of KDM4B in response to the cellular environment, and how this context-dependent expression may be translated into specific biological consequences in cancer and reproductive biology. Full article
(This article belongs to the Special Issue Histone Modification Enzymes and Long Noncoding RNAs in Cancer)
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Open AccessReview Writing Histone Monoubiquitination in Human Malignancy—The Role of RING Finger E3 Ubiquitin Ligases
Received: 24 December 2018 / Revised: 15 January 2019 / Accepted: 15 January 2019 / Published: 18 January 2019
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Abstract
There is growing evidence highlighting the importance of monoubiquitination as part of the histone code. Monoubiquitination, the covalent attachment of a single ubiquitin molecule at specific lysines of histone tails, has been associated with transcriptional elongation and the DNA damage response. Sites function [...] Read more.
There is growing evidence highlighting the importance of monoubiquitination as part of the histone code. Monoubiquitination, the covalent attachment of a single ubiquitin molecule at specific lysines of histone tails, has been associated with transcriptional elongation and the DNA damage response. Sites function as scaffolds or docking platforms for proteins involved in transcription or DNA repair; however, not all sites are equal, with some sites resulting in actively transcribed chromatin and others associated with gene silencing. All events are written by E3 ubiquitin ligases, predominantly of the RING (really interesting new gene) finger type. One of the most well-studied events is monoubiquitination of histone H2B at lysine 120 (H2Bub1), written predominantly by the RING finger complex RNF20-RNF40 and generally associated with active transcription. Monoubiquitination of histone H2A at lysine 119 (H2AK119ub1) is also well-studied, its E3 ubiquitin ligase constituting part of the Polycomb Repressor Complex 1 (PRC1), RING1B-BMI1, associated with transcriptional silencing. Both modifications are activated as part of the DNA damage response. Histone monoubiquitination is a key epigenomic event shaping the chromatin landscape of malignancy and influencing how cells respond to DNA damage. This review discusses a number of these sites and the E3 RING finger ubiquitin ligases that write them. Full article
(This article belongs to the Special Issue Histone Modification Enzymes and Long Noncoding RNAs in Cancer)
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Graphical abstract

Open AccessReview Enhancing the Anticancer Efficacy of Immunotherapy through Combination with Histone Modification Inhibitors
Genes 2018, 9(12), 633; https://doi.org/10.3390/genes9120633
Received: 10 November 2018 / Revised: 10 December 2018 / Accepted: 11 December 2018 / Published: 14 December 2018
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Abstract
In the nucleus of each cell, the DNA is wrapped around histone octamers, forming the so-called “nucleosomal core particles”. The histones undergo various modifications that influence chromatin structure and function, including methylation, acetylation, ubiquitination, phosphorylation, and SUMOylation. These modifications, known as epigenetic modifications [...] Read more.
In the nucleus of each cell, the DNA is wrapped around histone octamers, forming the so-called “nucleosomal core particles”. The histones undergo various modifications that influence chromatin structure and function, including methylation, acetylation, ubiquitination, phosphorylation, and SUMOylation. These modifications, known as epigenetic modifications (defined as heritable molecular determinants of phenotype that are independent of the DNA sequence), result in alterations of gene expression and changes in cell behavior. Recent work has shown that epigenetic drugs targeting histone deacetylation or methylation modulate the immune response and overcome acquired resistance to immunotherapy. A number of combination therapies involving immunotherapy and epigenetic drugs, which target histone deacetylation or methylation, are currently under various clinical/pre-clinical investigations and have shown promising anticancer efficacy. These combination therapies may provide a new strategy for achieving sustained anticancer efficacy and overcoming resistance. Full article
(This article belongs to the Special Issue Histone Modification Enzymes and Long Noncoding RNAs in Cancer)
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