Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma - An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing

Sep 21, 2026

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Neddylation is a post-translational modification implicated in human neoplasms, yet its relevance to kidney renal clear cell carcinoma (KIRC) is insufficiently characterized. Using validated bioinformatics analyses across TCGA pan-cancer data, genes linked to neddylation were clustered and assessed for CNVs, SNVs, expression, pathways, methylation, prognosis, drug response, immune infiltration, and oncogenic signaling. Target selection followed with MLN4924 inhibition and RNA sequencing plus in vitro assays. Results highlighted PSMB10 as overexpressed with adverse prognostic impact and suggested therapeutic target potential for KIRC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Introduction

Neddylation as a reversible post-translational modification

Background on NEDD8 and cullin-RING ligases (CRLs)

Abstract

Background

Methods

Results

Conclusion

pharmaceuticals Article Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing Dequan Liu 1, Guangzhen Wu 1, Shijin Wang 1, Xu Zheng 2,* and Xiangyu Che 1, * Citation: Liu, D.; Wu, G.; Wang, S.; Zheng, X.; Che, X. Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing. Pharmaceuticals 2024, 17, 635. [https://](https://)[ ](https://)[doi.org/10.3390/ph17050635](doi.org/10.3390/ph17050635) Academic Editors: Gary J. Stephens, Fuyi Wang and Andréia Machado Leopoldino Received: 9 April 2024 Revised: 7 May 2024 Accepted: 11 May 2024 Published: 15 May 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; liudq@dmu.edu.cn (D.L.); wuguangzhen@firsthosp-dmu.com (G.W.); wangsj01@dmu.edu.cn (S.W.) 2 Department of Cell Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116011, China * [Correspondence: zhengxu@dmu.edu.cn](Correspondence: zhengxu@dmu.edu.cn) (X.Z.); [chexiangyu@firsthosp-dmu.com](chexiangyu@firsthosp-dmu.com) (X.C.) Abstract: Background: Neddylation, a post-translational modification process, plays a crucial role in various human neoplasms. However, its connection with kidney renal clear cell carcinoma (KIRC) remains under-researched. Methods: We validated the Gene Set Cancer Analysis Lite (GSCALite) platform against The Cancer Genome Atlas (TCGA) database, analyzing 33 cancer types and their link with 17 neddylation-related genes. This included examining copy number variations (CNVs), single nucleotide variations (SNVs), mRNA expression, cellular pathway involvement, and methylation. Using Gene Set Variation Analysis (GSVA), we categorized these genes into three clusters and examined their impact on KIRC patient prognosis, drug responses, immune infiltration, and oncogenic pathways. Afterward, our objective is to identify genes that exhibit overexpression in KIRC and are associated with an adverse prognosis. After pinpointing the specific target gene, we used the specific inhibitor MLN4924 to inhibit the neddylation pathway to conduct RNA sequencing and related in vitro experiments to verify and study the specificity and potential mechanisms related to the target. This approach is geared towards enhancing our understanding of the prognostic importance of neddylation modification in KIRC. Results: We identified significant CNV, SNV, and methylation events in neddylation-related genes across various cancers, with notably higher expression levels observed in KIRC. Cluster analysis revealed a potential trade-off in the interactions among neddylation-related genes, where both high and low levels of gene expression are linked to adverse prognoses. This association is particularly pronounced concerning lymph node involvement, T stage classification, and Fustat score. Simultaneously, our research discovered that PSMB10 exhibits overexpression in KIRC when compared to normal tissues, negatively impacting patient prognosis. Through RNA sequencing and in vitro assays, we confirmed that the inhibition of neddylation modification could play a role in the regulation of various signaling pathways, thereby influencing the prognosis of KIRC. Moreover, our results underscore PSMB10 as a viable target for therapeutic intervention in KIRC, opening up novel pathways for the development of targeted treatment strategies. Conclusion: Thi

FAQs

Why study neddylation in kidney renal clear cell carcinoma (KIRC)?

Neddylation is known to influence multiple human neoplasms, but its relationship with KIRC has been under-researched. The study focuses on uncovering how neddylation-related genes associate with KIRC biology and prognosis.

What methods were used to analyze neddylation-related genes and their clinical impact?

The study validated the GSCALite platform against TCGA and evaluated 33 cancer types for links between 17 neddylation-related genes and multiple biological and clinical features, including CNVs, SNVs, expression, pathways, methylation, prognosis, drug response, immune infiltration, and oncogenic pathways. GSVA was used to cluster genes for KIRC assessment.

How did MLN4924 and RNA sequencing contribute to validating the findings?

After identifying a target gene associated with adverse prognosis, the researchers inhibited the neddylation pathway using MLN4924 and performed RNA sequencing alongside related in vitro experiments. This supported the idea that neddylation inhibition can regulate signaling pathways relevant to KIRC prognosis.

Sep 21, 2026

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