SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

• Published in: Kidney cancer journal 2022-01, 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: 1933-0863; 1933-0871
• DOI: 10.3233/KCA-220009

SET domain-containing protein 2 ( ) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. 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. To accomplish these objectives, we initially performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and -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. We observed decreased lysine methylation of the translation elongation factor eEF1A1. and are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of Globally, we observe differential expression of hundreds of proteins in WT versus -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 -mutated tumors predicted to have loss of function of the SET domain. Overall, these data suggest that -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.