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

• Published in: Kidney Cancer
• Main Authors: Robert Hapke, Lindsay Venton, Kristie Lindsay Rose, Quanhu Sheng, Anupama Reddy, Rebecca Prather, Angela Jones, W. Kimryn Rathmell, Scott M. Haake
• Format: Article
• Language: English
• Published: SAGE Publishing 2022-11-01
• Online Access: https://doi.org/10.3233/KCA-220009
• ISSN: 2468-4562; 2468-4570

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.