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IKCS 2019: Identifying a New Role for SETD2 in Clear Cell Renal Cell Carcinoma

By: Joseph Fanelli
Posted: Thursday, December 5, 2019

The SET domain-containing protein 2 (SETD2) may be associated with the dysregulation of protein translation in cases of clear cell renal cell carcinoma, according to findings presented at the 2019 International Kidney Cancer Symposium (IKCS) in Miami. Scott M. Haake, MD, of the Vanderbilt University School of Medicine, Nashville, and colleagues reported on this previously unidentified role for the protein-coding gene.

In this study, the investigators analyzed HKC human proximal tubule kidney cell lines, the “likely origin” for clear cell renal cell carcinoma. The authors identified wild-type and SETD2-knockout cells using stable isotope labeling via amino acids in cell culture. The proteins were trypsinized, and lysine-methylated peptides were immunoprecipitated. In total, more than 30,000 peptides were quantified, including more than 50 lysine-methylated peptides.

The study authors observed a decrease of lysine methylation of eukaryotic elongation factor 1A (eEF1A), including K165 trimethylation and K318 monomethylation. The functions of eEF1A included the delivery of aminoacyl-tRNA to the ribosome, with the function modulated through the lysine methyltransferases eEF1AKMT1-4. The investigators also observed the decreased expression of both eEF1AKMT2 and eEF1AKMT3 in SETD2-knockout cells, as well as global changes in protein translators and translational regulation.

Dr. Haake noted that the expression of eEF1AKMT2-3 may be “rescued” with the re-expression of wild-type SETD2 and SETD2 with SRI-domain mutation. “However, re-expression of SETD2 with SET-domain mutations fail to rescue eEF1AKMT2-3, suggesting their expression is dependent on the methyltransferase activity of SETD2,” he concluded.

Disclosure: The full disclosures of the study authors can be found at www.kidneycancer.org/.



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