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Cancers
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Protein Regulatory Mechanisms in Tumorigenesis
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Protein Regulatory Mechanisms in Tumorigenesis

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

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 7563

Special Issue Editors

Dr. Pengda Liu

E-Mail Website
Guest Editor
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Interests: cell signaling; cancer; kinase; E3 ligase/deubiquitinase; innate immunity; post-translational modification; protein–protein interaction
Dr. Wenjian Gan

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Interests: arginine methylation; ubiquitination; mTOR/AKT signaling; breast cancer; liver cancer

Special Issue Information

Dear Colleagues,

With the exception of inheritable diseases with genetic alternations, a large spectrum of human diseases are triggered by non-genetic changes in proteins, including the aberrancy of protein synthesis, deregulation of protein turnover, mislocalization of proteins in cellular compartments, and others. Post-translational modifications play an indispensable role in proper protein quality and functional control. Thus, understanding post-translational protein modifications in normal physiology and pathological conditions not only expands our knowledge on the diversity of the proteome, but also sheds new light on potential therapeutic opportunities.

In mammals, a plethora of post-translational modifications have been reported, including, but not limited to, phosphorylation, ubiquitylation, glycosylation, acetylation, methylation, SUMOylation, and hydroxylation, which are specifically governed by a subset of modifying enzymes. Most protein post-translational modifications are reversible and dynamically occur in a timely and spatially dependent manner. Abnormal post-translational protein modification events result in deregulated cell signaling, genome instability, and other aberrant biological processes, contributing to the development of human diseases, including cancers. Prior efforts in developing small-molecule inhibitors targeting aberrantly activated enzymes such as kinases show promise for cancer treatment. We hope this collection advances our understanding of the post-translational protein modification events driving disease and their regulatory mechanisms, in order to facilitate the identification of novel drug targets with potential for the development of novel therapies.

Dr. Pengda Liu
Dr. Wenjian Gan
Guest Editors

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 short 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

  • protein regulation
  • post-translational modifications
  • cell signaling
  • genome instability
  • tumorigenesis
  • cancer therapy

Published Papers (4 papers)

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Research

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18 pages, 6218 KiB  
Article
Inhibition of O-GlcNAcylation Reduces Cell Viability and Autophagy and Increases Sensitivity to Chemotherapeutic Temozolomide in Glioblastoma
by Amanda V. Leonel, Frederico Alisson-Silva, Ronan C. M. Santos, Rodrigo P. Silva-Aguiar, Julia C. Gomes, Gabriel M. C. Longo, Bruna M. Faria, Mariana S. Siqueira, Miria G. Pereira, Andreia Vasconcelos-dos-Santos, Luciana B. Chiarini, Chad Slawson, Celso Caruso-Neves, Luciana Romão, Leonardo H. Travassos, Katia Carneiro, Adriane R. Todeschini and Wagner B. Dias
Cancers 2023, 15(19), 4740; https://doi.org/10.3390/cancers15194740 - 27 Sep 2023
Cited by 6 | Viewed by 1505
Abstract
Glioblastoma (GB) is the most aggressive primary malignant brain tumor and is associated with short survival. O-GlcNAcylation is an intracellular glycosylation that regulates protein function, enzymatic activity, protein stability, and subcellular localization. Aberrant O-GlcNAcylation is related to the tumorigenesis of different tumors, and [...] Read more.
Glioblastoma (GB) is the most aggressive primary malignant brain tumor and is associated with short survival. O-GlcNAcylation is an intracellular glycosylation that regulates protein function, enzymatic activity, protein stability, and subcellular localization. Aberrant O-GlcNAcylation is related to the tumorigenesis of different tumors, and mounting evidence supports O-GlcNAc transferase (OGT) as a potential therapeutic target. Here, we used two human GB cell lines alongside primary human astrocytes as a non-tumoral control to investigate the role of O-GlcNAcylation in cell proliferation, cell cycle, autophagy, and cell death. We observed that hyper O-GlcNAcylation promoted increased cellular proliferation, independent of alterations in the cell cycle, through the activation of autophagy. On the other hand, hypo O-GlcNAcylation inhibited autophagy, promoted cell death by apoptosis, and reduced cell proliferation. In addition, the decrease in O-GlcNAcylation sensitized GB cells to the chemotherapeutic temozolomide (TMZ) without affecting human astrocytes. Combined, these results indicated a role for O-GlcNAcylation in governing cell proliferation, autophagy, cell death, and TMZ response, thereby indicating possible therapeutic implications for treating GB. These findings pave the way for further research and the development of novel treatment approaches which may contribute to improved outcomes and increased survival rates for patients facing this challenging disease. Full article
(This article belongs to the Special Issue Protein Regulatory Mechanisms in Tumorigenesis)
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14 pages, 2947 KiB  
Article
TRAF6 Promotes PRMT5 Activity in a Ubiquitination-Dependent Manner
by Liu Liu, Shasha Yin and Wenjian Gan
Cancers 2023, 15(9), 2501; https://doi.org/10.3390/cancers15092501 - 27 Apr 2023
Cited by 1 | Viewed by 1709
Abstract
Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme generating symmetric dimethylarginine (sDMA) on numerous substrates, through which it regulates many cellular processes, such as transcription and DNA repair. Aberrant expression and activation of PRMT5 is frequently observed in various human cancers and [...] Read more.
Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme generating symmetric dimethylarginine (sDMA) on numerous substrates, through which it regulates many cellular processes, such as transcription and DNA repair. Aberrant expression and activation of PRMT5 is frequently observed in various human cancers and associated with poor prognosis and survival. However, the regulatory mechanisms of PRMT5 remain poorly understood. Here, we report that TRAF6 serves as an upstream E3 ubiquitin ligase to promote PRMT5 ubiquitination and activation. We find that TRAF6 catalyzes K63-linked ubiquitination of PRMT5 and interacts with PRMT5 in a TRAF6-binding-motif-dependent manner. Moreover, we identify six lysine residues located at the N-terminus as the primarily ubiquitinated sites. Disruption of TRAF6-mediated ubiquitination decreases PRMT5 methyltransferase activity towards H4R3 in part by impairing PRMT5 interaction with its co-factor MEP50. As a result, mutating the TRAF6-binding motifs or the six lysine residues significantly suppresses cell proliferation and tumor growth. Lastly, we show that TRAF6 inhibitor enhances cellular sensitivity to PRMT5 inhibitor. Therefore, our study reveals a critical regulatory mechanism of PRMT5 in cancers. Full article
(This article belongs to the Special Issue Protein Regulatory Mechanisms in Tumorigenesis)
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Review

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17 pages, 1412 KiB  
Review
G1 Dynamics at the Crossroads of Pluripotency and Cancer
by Dalia Fleifel and Jeanette Gowen Cook
Cancers 2023, 15(18), 4559; https://doi.org/10.3390/cancers15184559 - 14 Sep 2023
Cited by 2 | Viewed by 1271
Abstract
G1 cell cycle phase dynamics are regulated by intricate networks involving cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, which control G1 progression and ensure proper cell cycle transitions. Moreover, adequate origin licensing in G1 phase, the first committed step of DNA replication in [...] Read more.
G1 cell cycle phase dynamics are regulated by intricate networks involving cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, which control G1 progression and ensure proper cell cycle transitions. Moreover, adequate origin licensing in G1 phase, the first committed step of DNA replication in the subsequent S phase, is essential to maintain genome integrity. In this review, we highlight the intriguing parallels and disparities in G1 dynamics between stem cells and cancer cells, focusing on their regulatory mechanisms and functional outcomes. Notably, SOX2, OCT4, KLF4, and the pluripotency reprogramming facilitator c-MYC, known for their role in establishing and maintaining stem cell pluripotency, are also aberrantly expressed in certain cancer cells. In this review, we discuss recent advances in understanding the regulatory role of these pluripotency factors in G1 dynamics in the context of stem cells and cancer cells, which may offer new insights into the interconnections between pluripotency and tumorigenesis. Full article
(This article belongs to the Special Issue Protein Regulatory Mechanisms in Tumorigenesis)
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14 pages, 1075 KiB  
Review
Regulation of EWSR1-FLI1 Function by Post-Transcriptional and Post-Translational Modifications
by Le Yu, Ian J. Davis and Pengda Liu
Cancers 2023, 15(2), 382; https://doi.org/10.3390/cancers15020382 - 6 Jan 2023
Cited by 5 | Viewed by 2647
Abstract
Ewing sarcoma is the second most common bone tumor in childhood and adolescence. Currently, first-line therapy includes multidrug chemotherapy with surgery and/or radiation. Although most patients initially respond to chemotherapy, recurrent tumors become treatment refractory. Pathologically, Ewing sarcoma consists of small round basophilic [...] Read more.
Ewing sarcoma is the second most common bone tumor in childhood and adolescence. Currently, first-line therapy includes multidrug chemotherapy with surgery and/or radiation. Although most patients initially respond to chemotherapy, recurrent tumors become treatment refractory. Pathologically, Ewing sarcoma consists of small round basophilic cells with prominent nuclei marked by expression of surface protein CD99. Genetically, Ewing sarcoma is driven by a fusion oncoprotein that results from one of a small number of chromosomal translocations composed of a FET gene and a gene encoding an ETS family transcription factor, with ~85% of tumors expressing the EWSR1::FLI1 fusion. EWSR1::FLI1 regulates transcription, splicing, genome instability and other cellular functions. Although a tumor-specific target, EWSR1::FLI1-targeted therapy has yet to be developed, largely due to insufficient understanding of EWSR1::FLI1 upstream and downstream signaling, and the challenges in targeting transcription factors with small molecules. In this review, we summarize the contemporary molecular understanding of Ewing sarcoma, and the post-transcriptional and post-translational regulatory mechanisms that control EWSR1::FLI1 function. Full article
(This article belongs to the Special Issue Protein Regulatory Mechanisms in Tumorigenesis)
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