WTAP's Dual Role in Disease: Orchestrating Inflammation in Rheumatoid Arthritis and Challenging Renal Clear Cell Carcinoma Outcomes

Abstract

The study by Wang et al. titled “WTAP-Mediated m6A Modification of TRAIL-DR4 Suppresses MH7A Cell Apoptosis” highlights the critical role of Wilms tumor 1-associating protein (WTAP), a regulatory component of the N6-methyladenosine (m6A) methyltransferase complex, forms a functional unit with METTL3 and METTL14 to mediate m6A deposition [1]. WTAP promotes mRNA destabilization of TNF-related apoptosis-inducing ligand death receptor 4 (TRAIL-DR4), thereby inhibiting apoptosis and contributing to synovial hyperplasia and persistent inflammation. These findings are consistent with earlier reports demonstrating WTAP's role in inflammatory regulation through m6A-dependent mechanisms, including modulation of cytokine expression in activated macrophages [2]. Building on these foundations, our current investigation expands the scope of WTAP's functional landscape by exploring its relationship with the tumor immune microenvironment, in parallel with its role in inflammatory signaling. This integrated approach is crucial, given the mechanistic overlaps between chronic inflammation and tumorigenesis [3].

Our study utilized a comprehensive multi-omics approach to elucidate the impact of WTAP expression on genetic landscapes, biological processes, and drug responses in Kidney Renal Clear Cell Carcinoma (KIRC), leveraging data from the TCGA database. We extracted WTAP expression profiles from KIRC patients and visualized the top 20 affected genes using a waterfall plot (Figure 1A). The genetic alterations included oncogenes, tumor suppressor genes, splice site mutations, and frameshift variants, providing a broad genomic context. Comparative analysis of mRNA (Figure 1B) and protein (Figure 1C) expression levels between normal and KIRC tissues revealed a significant reduction in WTAP expression in tumor samples, consistent across TCGA and proteomic datasets.

Further prognostic analysis using Kaplan–Meier curves demonstrated that low WTAP expression in KIRC is associated with poor overall survival and progression-free survival (Figure 1D,E). This suggests that WTAP's function may be highly tissue- and disease-specific, differing from its anti-apoptotic and anti-inflammatory role in RA. To explore the immunological underpinnings, we assessed T-cell interactions across six independent databases, consistently identifying a positive correlation between WTAP expression and T-cell activation (Figure 1F). We extended our analysis to T-cell-related biological processes, evaluating activation, homeostasis, proliferation, and chemotaxis in KIRC patients stratified by WTAP expression levels (Figure 1G). This contrasts with the MH7A cell model, where WTAP-mediated m6A modification of TRAIL-DR4 inhibits apoptosis and modulates inflammation. Additionally, we interrogated the PRISM Pharmacogenomic Database to assess drug sensitivity and resistance, identifying 20 drugs where high WTAP expression predicted increased sensitivity and 20 where it predicted resistance (Figure 1H). Correlation analyses with IC50 values in the TCGA_KIRC cohort confirmed these trends, with the highly sensitive drug ZK93426 exhibiting negative regulation and procaine showing positive regulation with WTAP levels (Figure 1I). These pharmacogenomic insights suggest that WTAP expression could serve as a biomarker for tailoring therapy in KIRC, contrasting with its therapeutic targeting strategy in the MH7A cell model.

These findings challenge the uniform application of epigenetic targets like WTAP across malignancies. While the WTAP study demonstrates its role in suppressing apoptosis and inflammation in RA via TRAIL-DR4 mRNA destabilization—confirmed by MeRIP-qPCR and actinomycin D assays [1]—the low WTAP levels in KIRC may reflect a loss of regulatory control over apoptosis and inflammatory pathways, contributing to disease progression. This discrepancy may arise from differences in tumor microenvironment, genetic alterations, or the interplay between m6A modification, immune checkpoints, and inflammation beyond TRAIL-DR4, as seen in other cancers where m6A dysregulation influences tumor immunity [2].

This editorial advocates for a context-specific approach to targeting epigenetic regulators in oncology, with a particular emphasis on their inflammatory dimensions. The success of WTAP modulation in RA should not be extrapolated to KIRC without further validation. Future research should leverage multi-omics analyses to dissect the pathways linking WTAP, m6A modification, immune responses, and inflammation in KIRC, potentially identifying compensatory mechanisms or alternative targets. Integrating these findings with clinical trials could refine therapeutic strategies, ensuring that WTAP agonists or antagonists are tailored to the specific disease context and its inflammatory profile.

In conclusion, the low WTAP expression in KIRC, as revealed by our data, contrasts with its protective role in RA and invites a nuanced exploration of its therapeutic potential, particularly in the context of inflammation and the tumor immune microenvironment. Collaborative efforts to bridge epigenetic, immunological, and inflammatory research will be essential to unlocking precision medicine's full potential across diverse cancer landscapes.

C.-Y.W., P.-H.C., and Y.C. conceived and drafted the manuscript; C.-Y.W. and C.-J.L. provided valuable discussion; C.-J.L. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

The authors have nothing to report.

The authors have nothing to report.

The authors declare no conflicts of interest.