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Ubiquitin Proteasome Pathway Transcriptome in Epithelial Ovarian Cancer

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cancers Review Ubiquitin Proteasome Pathway Transcriptome in Epithelial Ovarian Cancer Jerry Vriend 1,* and Mark W. Nachtigal 2,3,4 1 Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada 2 Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; [email protected] 3 Department of Obstetrics, Gynecology & Reproductive Sciences, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada 4 CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada * Correspondence: [email protected]; Tel.: +1-204-789-3732 Simple Summary: In this review, public datasets were mined in an attempt to identify genes that code for proteins of the ubiquitin proteasome system that can be used as therapeutic targets in high- grade serous ovarian cancer. In this study, we found that more than 50 genes coding for ubiquitin ligases and more than 100 for ubiquitin ligase adaptors were differentially expressed between the low malignant potential tumors and the malignant invasive ovarian tumors. We conclude that several genes coding for the ubiquitin ligases and their adaptors have a potential to serve as therapeutic targets in high-grade serous ovarian cancer. Abstract: In this article, we reviewed the transcription of genes coding for components of the ubiquitin proteasome pathway in publicly available datasets of epithelial ovarian cancer (EOC). Citation: Vriend, J.; Nachtigal, M.W. KEGG analysis was used to identify the major pathways distinguishing EOC of low malignant Ubiquitin Proteasome Pathway potential (LMP) from invasive high-grade serous ovarian carcinomas (HGSOC), and to identify the Transcriptome in Epithelial Ovarian components of the ubiquitin proteasome system that contributed to these pathways. We identified Cancer. Cancers 2021, 13, 2659. elevated transcription of several genes encoding ubiquitin conjugases associated with HGSOC. Fifty- https://doi.org/10.3390/ eight genes coding for ubiquitin ligases and more than 100 genes encoding ubiquitin ligase adaptors cancers13112659 that were differentially expressed between LMP and HGSOC were also identified. Many differentially Academic Editors: George Mosialos expressed genes encoding E3 ligase adaptors were Cullin Ring Ligase (CRL) adaptors, and 64 of and Deborah J. Marsh them belonged to the Cullin 4 DCX/DWD family of CRLs. The data suggest that CRLs play a role in HGSOC and that some of these proteins may be novel therapeutic targets. Differential expression of Received: 3 April 2021 genes encoding deubiquitinases and proteasome subunits was also noted. Accepted: 24 May 2021 Published: 28 May 2021 Keywords: ovarian cancer; transcriptome; ubiquitin ligase Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Gene expression of epithelial ovarian cancers (EOCs) has been studied in terms of the major histological subgroups as well as classifications based on clinical outcome. These studies generated large datasets which included gene expression data that went well beyond the objectives of the original studies. One study of EOC that provided clinical as Copyright: © 2021 by the authors. well as molecular subtypes was the study of Tothill et al. (2008) [1]. In the original Tothill Licensee MDPI, Basel, Switzerland. manuscript, six molecular subtypes of ovarian cancer (C1–C6) were described based on This article is an open access article gene expression [1], four of which were high-grade serous ovarian cancer (HGSOC) tumors. distributed under the terms and The Tothill molecular subtypes are not found consistently. Two publicly available (see conditions of the Creative Commons methods) datasets are the Anglesio dataset [2] and the Bowtell dataset [1]. The Anglesio Attribution (CC BY) license (https:// dataset reports gene expression in low malignant potential (LMP) vs. a HGSOC invasive creativecommons.org/licenses/by/ (INV) group of tumors; the Bowtell dataset reports gene expression in LMP serous tumors 4.0/). Cancers 2021, 13, 2659. https://doi.org/10.3390/cancers13112659 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 24 Cancers 2021, 13, 2659 2 of 22 HGSOC invasive (INV) group of tumors; the Bowtell dataset reports gene expression in LMP serous tumors vs. malignant (MAL) ovarian tumors that include histotypes other than HGSOC. In this study, we focused primarily on the Anglesio dataset in order to study differentiallyvs. malignant expressed (MAL) genes ovarian between tumors LMP that and include HGSOC. histotypes other than HGSOC. In thisThe study, ubiquitin we focused proteasome primarily system on plays the Anglesio a role in dataset regulating in order proteins to study which differentially are risk factorsexpressed in EOC genes [3–5]. between Ubiquitin LMP is added and HGSOC. to proteins via three steps involving a ubiquitin activatingThe enzyme ubiquitin (E1), proteasome a ubiquitin system conjugase plays (E2), a role and in a regulatingubiquitin ligase proteins (E3) which (Figure are 1). risk Ubiquitinationfactors in EOC of proteins [3–5]. Ubiquitin provides is a added signal tofor proteins various viacellular three processes steps involving including a ubiquitin deg- radationactivating by the enzyme proteasome, (E1), a regulation ubiquitinconjugase of the cell (E2),cycle, and and a modulation ubiquitin ligase of transcription. (E3) (Figure 1 ). UbiquitinationUbiquitination may of be proteins reversed provides by deubiqutinases. a signal for various cellular processes including degra- dation by the proteasome, regulation of the cell cycle, and modulation of transcription. Ubiquitination may be reversed by deubiqutinases. Figure 1. Components of the ubiquitin proteasome pathway in protein degradation. Figure 1. Components of the ubiquitin proteasome pathway in protein degradation. Herein, we reviewed the gene expression of ubiquitin conjugases, ubiquitin ligases, ubiquitinHerein, ligasewe reviewed adaptors, the and gene deubiquitinases expression of ubiquitin in the publicly conjugases, available ubiquitin EOC expressionligases, ubiquitindatasets ligase comparing adaptors, LMP and and deubiquitinases HGSOC and relatein the the publicly data to available the available EOC literature.expression We datasetsalso reviewed comparing the LMP data and for HGSOC the gene and expression relate the of data 43 proteasome to the available subunits. literature. We related We alsothe reviewed expression the data of these for the genes gene to expressi knownon pathways of 43 proteasome in EOC, comparedsubunits. We gene related expression the expressionbetween of LMP these and genes HGSOC, to known and pathways made suggestions in EOC, compared for potential gene therapeutic expression targets between based LMPon and these HGSOC, analyses. and We made found suggestions that the transcriptionfor potential therapeutic of several ubiquitin targets based conjugases on these and analyses.numerous We found ubiquitin that ligases the transcription was different of inseveral LMP vs.ubiquitin HGSOC. conjugases This is consistent and numerous with the ubiquitinview that ligases the mechanismwas different of in tumorigenesis LMP vs. HGSOC. and cellular This is originconsistent may with be different the view between that thethese mechanism two groups. of tumorigenesis and cellular origin may be different between these two groups. 2. Materials and Methods 2. MaterialsIn addition and Methods to reviewing the literature on ubiquitin ligases and EOC, we analyzed theIn relevant addition publicly to reviewing available the literature datasets on of geneubiquitin expression ligases inand EOC EOC, comparing we analyzed LMP the and relevantHGSOC. publicly The expression available profilingdatasets datasetsof gene usedexpression are the in Anglesio EOC comparing dataset (N =LMP 90) [and2] and N HGSOC.the Bowtell The expression dataset ( profiling= 285) [1 datase], bothts available used are throughthe Anglesio the R2 dataset Genomics (N = 90) Analysis [2] and and Visualization Platform (R2-GAVP) (http://R2.amc.nl, accessed on 20 January 2021). The the Bowtell dataset (N = 285) [1], both available through the R2 Genomics Analysis and data from the Bowtell dataset were reclustered by Anglesio et al. [2] into 2 groups, 32 LMP Visualization Platform (R2-GAVP) (http://R2.amc.nl, accessed on 20 January 2021). The and 58 HGSOC, referred to as the INV cluster. For the purposes of this review, we will refer data from the Bowtell dataset were reclustered by Anglesio et al. [2] into 2 groups, 32 LMP to the INV group as HGSOC. Since the malignant group in the Bowtell dataset included and 58 HGSOC, referred to as the INV cluster. For the purposes of this review, we will histotypes other than HGSOC, in the current study, which is a comparison of LMP and refer to the INV group as HGSOC. Since the malignant group in the Bowtell dataset in- HGSOC gene expression on the ubiquitin proteasome system (UPS), we focused on the cluded histotypes other than HGSOC, in the current study, which is a comparison of LMP Anglesio dataset. However, in several instances, we monitored the Bowtell dataset (LMP vs. MAL) for comparative purposes. The Bowtell data included the 60 HGSOC invasive samples of the Anglesio dataset and 18 of the 30 LMP samples of the Anglesio dataset. The Cancers 2021, 13, 2659 3 of 22 datasets as presented in the
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  • Neddylation: a Novel Modulator of the Tumor Microenvironment Lisha Zhou1,2*†, Yanyu Jiang3†, Qin Luo1, Lihui Li1 and Lijun Jia1*

    Neddylation: a Novel Modulator of the Tumor Microenvironment Lisha Zhou1,2*†, Yanyu Jiang3†, Qin Luo1, Lihui Li1 and Lijun Jia1*

    Zhou et al. Molecular Cancer (2019) 18:77 https://doi.org/10.1186/s12943-019-0979-1 REVIEW Open Access Neddylation: a novel modulator of the tumor microenvironment Lisha Zhou1,2*†, Yanyu Jiang3†, Qin Luo1, Lihui Li1 and Lijun Jia1* Abstract Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition. Keywords: Neddylation, Tumor microenvironment, Tumor-derived factors, Cancer-associated fibroblasts, Cancer- associated endothelial cells, Immune cells Introduction Overall, binding of NEDD8 molecules to target proteins Neddylation is a reversible covalent conjugation of an can affect their stability, subcellular localization, conform- ubiquitin-like molecule NEDD8 (neuronal precursor ation and function [4]. The best-characterized substrates cell-expressed developmentally down-regulated protein of neddylation are the cullin subunits of Cullin-RING li- 8) to a lysine residue of the substrate protein [1, 2].