SETD2 Regulates the Methylation of Translation Elongation Factor eEF1A1 in Clear Cell Renal Cell Carcinoma1

• Published in: Kidney cancer 2022-11, Vol.6 (3), p.179-193
• Main Authors: Hapke, Robert, Venton, Lindsay, Rose, Kristie Lindsay, Sheng, Quanhu, Reddy, Anupama, Prather, Rebecca, Jones, Angela, Rathmell, W. Kimryn, Haake, Scott M.
• Format: Article
• Language: English
• ISSN: 2468-4562; 2468-4570
• DOI: 10.3233/KCA-220009

BACKGROUND: SET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. OBJECTIVE: Initially, we sought to explore SETD2-dependent changes in lysine methylation of proteins in proximal renal tubule cells. Subsequently, we focused on changes in lysine methylation of the translation elongation factor eEF1A1. METHODS: To accomplish these objectives, we initially performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells and later focused our studies on eEF1A1 as well as the expression of lysine methyltransferases that regulate its lysine methylation. RESULTS: We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors predicted to have loss of function of the SET domain. CONCLUSION: Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymatic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.