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Jumonji Domain-Containing Proteins in Cancer Progression

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 16853

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Special Issue Editors

Prof. Dr. Sangphil Oh

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Guest Editor

Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Interests: Jumonji C domain-containing (JMJD) proteins; histones; epigenome; gene expression

Dr. William Berry

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Guest Editor

Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Interests: kinase; transcription factor; animal model; genetic engineering; cancer; molecular biology

Special Issue Information

Dear Colleagues,

Cancer cell growth is largely driven by the silencing of tumor-suppressor genes and/or the expression of oncogenes. Considerable amount of research has been undertaken to determine how these class of genes are regulated. Histone lysine methylation was first discovered in the 1960’s which gave rise to the study of enzymes named histone methyltransferases which have the ability to methylate specific lysine residues on histones to control gene transcription. It was long believed that lysine methylation was irreversible, until 2004 when the first histone demethylase was discovered. Since that time, Jumonji C Domain-Containing (JMJD) proteins were discovered which function to remove methyl groups from lysine and arginine residues on histones H3 and H4 to regulate gene expression. Similar to histone methyltransferases, histone demethylases have been implicated in cancer development and progression. Therefore, it is important to further determine whether JMJD proteins are potential therapeutic targets.

In this Special Issue on “Junomji Domain-Containing Proteins in Cancer Progression”, many aspects of the JMJD family proteins will be highlighted. We would like to invite scientists to submit manuscripts focusing on the JMJD proteins in cancer progression. Contributions to this Special Issue will cover in the format of reviews, original research articles, communications, and concept papers.

Prof. Dr. Sangphil Oh
Dr. William Berry
Guest Editors

Keywords

Histones
Epigenome
Epigenetics
Cancer
Gene expression
Jumonji Domain-Containing Proteins Demethylation
Hydroxylation
JMJD
KDM

Published Papers (5 papers)

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Research

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13 pages, 2041 KiB

Open AccessCommunication

Insights into a Cancer-Target Demethylase: Substrate Prediction through Systematic Specificity Analysis for KDM3A

by Anand Chopra, William G. Willmore and Kyle K. Biggar

Biomolecules 2022, 12(5), 641; https://doi.org/10.3390/biom12050641 - 27 Apr 2022

Cited by 3 | Viewed by 2626

Abstract

Jumonji C (JmjC) lysine demethylases (KDMs) catalyze the removal of methyl (-CH₃) groups from modified lysyl residues. Several JmjC KDMs promote cancerous properties and these findings have primarily been in relation to histone demethylation. However, the biological roles of these enzymes are increasingly being shown to also be attributed to non-histone demethylation. Notably, KDM3A has become relevant to tumour progression due to recent findings of this enzyme’s role in promoting cancerous phenotypes, such as enhanced glucose consumption and upregulated mechanisms of chemoresistance. To aid in uncovering the mechanism(s) by which KDM3A imparts its oncogenic function(s), this study aimed to unravel KDM3A substrate specificity to predict high-confidence substrates. Firstly, substrate specificity was assessed by monitoring activity towards a peptide permutation library of histone H3 di-methylated at lysine-9 (i.e., H3K9me2). From this, the KDM3A recognition motif was established and used to define a set of high-confidence predictions of demethylation sites from within the KDM3A interactome. Notably, this led to the identification of three in vitro substrates (MLL1, p300, and KDM6B), which are relevant to the field of cancer progression. This preliminary data may be exploited in further tissue culture experiments to decipher the avenues by which KDM3A imparts cancerous phenotypes. Full article

(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)

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10 pages, 23469 KiB

Open AccessArticle

Elevated Expression of JMJD5 Protein Due to Decreased miR-3656 Levels Contributes to Cancer Stem Cell-Like Phenotypes under Overexpression of Cancer Upregulated Gene 2

by Natpaphan Yawut, Il-Rae Cho, Phatcharaporn Budluang, Sirichat Kaowinn, Chutima Kaewpiboon, Byeoleun Jeon, Sang-Woo Kim, Ho Young Kang, Min-Kyung Kang, Sang Seok Koh and Young-Hwa Chung

Biomolecules 2022, 12(1), 122; https://doi.org/10.3390/biom12010122 - 12 Jan 2022

Cited by 2 | Viewed by 1822

Abstract

Overexpression of cancer upregulated gene (CUG) 2 induces cancer stem cell-like phenotypes, such as enhanced epithelial-mesenchymal transition, sphere formation, and doxorubicin resistance. However, the precise mechanism of CUG2-induced oncogenesis remains unknown. We evaluated the effects of overexpression of CUG2 on microRNA levels using a microRNA microarray. Levels of miR-3656 were decreased when CUG2 was overexpressed; on the basis of this result, we further examined the target proteins of this microRNA. We focused on Jumonji C domain-containing protein 5 (JMJD5), as it has not been previously reported to be targeted by miR-3656. When CUG2 was overexpressed, JMJD5 expression was upregulated compared to that in control cells. A 3′ untranslated region (UTR) assay revealed that an miR-3656 mimic targeted the JMJD5 3′UTR, but the miR-3656 mimic failed to target a mutant JMJD5 3′UTR, indicating that miR-3656 targets the JMJD5 transcript. Administration of the miR-3656 mimic decreased the protein levels of JMD5 according to Western blotting. Additionally, the miR-3656 mimic decreased CUG2-induced cell migration, evasion, and sphere formation and sensitized the cells to doxorubicin. Suppression of JMJD5, with its small interfering RNA, impeded CUG2-induced cancer stem cell-like phenotypes. Thus, overexpression of CUG2 decreases miR-3656 levels, leading to upregulation of JMJD5, eventually contributing to cancer stem cell-like phenotypes. Full article

(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)

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Review

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21 pages, 1459 KiB

Open AccessReview

The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update

by Gianluca Malagraba, Mahdieh Yarmohammadi, Aadil Javed, Carles Barceló and Teresa Rubio-Tomás

Biomolecules 2022, 12(3), 462; https://doi.org/10.3390/biom12030462 - 17 Mar 2022

Cited by 15 | Viewed by 5333

Abstract

Epigenetic mechanisms are known to play a key role in cancer progression. Specifically, histone methylation involves reversible post-translational modification of histones that govern chromatin structure remodelling, genomic imprinting, gene expression, DNA damage repair, and meiotic crossover recombination, among other chromatin-based activities. Demethylases are enzymes that catalyse the demethylation of their substrate using a flavin adenine dinucleotide-dependent amine oxidation process. Lysine-specific demethylase 1 (LSD1) and its homolog, lysine-specific demethylase 2 (LSD2), are overexpressed in a variety of human cancer types and, thus, regulate tumour progression. In this review, we focus on the literature from the last 5 years concerning the role of LSD1 and LSD2 in the main gastrointestinal cancers (i.e., gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer). Full article

(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)

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21 pages, 5527 KiB

Open AccessReview

The Novel Protease Activities of JMJD5–JMJD6–JMJD7 and Arginine Methylation Activities of Arginine Methyltransferases Are Likely Coupled

by Haolin Liu, Pengcheng Wei, Qianqian Zhang, Zhongzhou Chen, Junfeng Liu and Gongyi Zhang

Biomolecules 2022, 12(3), 347; https://doi.org/10.3390/biom12030347 - 23 Feb 2022

Cited by 26 | Viewed by 3036

Abstract

The surreptitious discoveries of the protease activities on arginine-methylated targets of a subfamily of Jumonji domain-containing family including JMJD5, JMJD6, and JMJD7 pose several questions regarding their authenticity, function, purpose, and relations with others. At the same time, despite several decades of efforts and massive accumulating data regarding the roles of the arginine methyltransferase family (PRMTs), the exact function of this protein family still remains a mystery, though it seems to play critical roles in transcription regulation, including activation and inactivation of a large group of genes, as well as other biological activities. In this review, we aim to elucidate that the function of JMJD5/6/7 and PRMTs are likely coupled. Besides roles in the regulation of the biogenesis of membrane-less organelles in cells, they are major players in regulating stimulating transcription factors to control the activities of RNA Polymerase II in higher eukaryotes, especially in the animal kingdom. Furthermore, we propose that arginine methylation by PRMTs could be a ubiquitous action marked for destruction after missions by a subfamily of the Jumonji protein family. Full article

(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)

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19 pages, 1064 KiB

Open AccessEditor’s ChoiceReview

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

by Hans Felix Staehle, Heike Luise Pahl and Jonas Samuel Jutzi

Biomolecules 2021, 11(12), 1911; https://doi.org/10.3390/biom11121911 - 20 Dec 2021

Cited by 4 | Viewed by 3253

Abstract

Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting. Full article

(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)

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