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SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma
Robert Hapke1, Lindsay Venton2, Kristie Lindsay Rose3
1Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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.
Insights
Mutations in SET domain-containing protein 2 (SETD2) in kidney cancer disrupt protein lysine methylation, particularly affecting translation elongation factor eEF1A1. This dysregulation of protein translation contributes to the cancer
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- SET domain-containing protein 2 (SETD2) is frequently mutated in renal cell carcinoma.
- SETD2 plays a role in methylating histone and non-histone proteins.
Purpose of the Study:
- To investigate SETD2-dependent lysine methylation changes in proximal renal tubule cells.
- To specifically examine alterations in the methylation of translation elongation factor eEF1A1.
Main Methods:
- Performed system-wide analysis of protein lysine-methylation and expression in wild-type and SETD2-knockout kidney cells.
- Focused on eEF1A1 and its regulating lysine methyltransferases.
Main Results:
- Observed decreased lysine methylation of eEF1A1.
- Demonstrated SETD2 SET-domain function is crucial for EEF1AKMT2 and EEF1AKMT3 expression.
- Noted differential expression of hundreds of proteins, including those involved in translation, in SETD2-knockout cells.
- Found decreased progression-free survival and loss of EEF1AKMT2 expression in SETD2-mutated tumors.
Conclusions:
- SETD2-mutated clear cell renal cell carcinoma (ccRCC) exhibits dysregulated protein translation due to loss of SETD2's enzymatic function.
- This dysregulation is a potential driver of the transformed phenotype in ccRCC.
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