Abstract
Succinylation is a newly discovered and multienzyme-regulated post-translational modification (PTM) that is associated with the initiation and progression of cancer. Currently, no systematic analyses on the role of succinylation regulators in tumors have been reported. In this study, we performed a comprehensive pan-cancer analysis on four well-known succinylation regulators (CPT1A, KAT2A, SIRT5, and SIRT7). We found that these regulators played specific and critical roles in the prognosis of clear cell renal cell carcinoma (ccRCC). We constructed a risk score (RS) based on two independent prognostic prediction factors, CPT1A and KAT2A, and subsequently developed a nomogram model containing the RS, which showed good accuracy in the prediction of overall survival (OS) in ccRCC patients. Furthermore, we used the similar expression pattern of four succinylation regulators according to consensus clustering analysis to divide the patients into three clusters that exhibited prominently different OS as well as clinicopathological characteristics. Differently expressed genes (DEGs) and pathway enrichment analyses of three clusters indicated that succinylation regulators might promote malignant progression of ccRCC by regulating the infiltration of immune cells and RNA N6-methyladenosine (m6A) methylation. Importantly, our data suggest that CPT1A and SIRT5 might up-regulate and down-regulate the expression of LRPPRC and EIF3B, respectively. Our study systematically analyzed the prognostic predictive values of four succinylation regulators and revealed their potential mechanisms in ccRCC aggressiveness. These data provide new insight into the understanding of succinylation modification and present clinical evidence for its role in ccRCC treatments.
Highlights
Renal cell carcinoma (RCC) is one of the most common carcinomas with a continuously increasing incidence over several decades, in which clear cell renal cell carcinoma accounts for approximately 75–80% (Shuch et al, 2015; Makhov et al, 2018)
We found that lysine acetyltransferase 2A (KAT2A) was prominently upregulated in all types of tumors compared to the corresponding normal tissues
Univariate Cox regression analysis showed that the overall survival (OS) of patients with kidney renal clear cell carcinoma (KIRC), but not other tumor types, was associated with all four regulators (P < 0.05) (Figure 1B and Supplementary Table S4)
Summary
Renal cell carcinoma (RCC) is one of the most common carcinomas with a continuously increasing incidence over several decades, in which clear cell renal cell carcinoma (ccRCC) accounts for approximately 75–80% (Shuch et al, 2015; Makhov et al, 2018). Curative resection is the most effective therapy for ccRCC. The 5 years survival rate for patients with advanced ccRCC is only 11.7% (Siegel et al, 2017) and so there is an urgent need for the development of novel therapeutic options. New treatments such as anti-angiogenesis drugs and immune checkpoint inhibitors are recently recommended as first-line therapies, the objective response rate (ORR) is unsatisfactory yet (Angulo and Shapiro, 2019). It is necessary to develop novel prognostic biomarkers of ccRCC to screen out those patients with poor prognosis for more positive treatment
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