Abstract 6794: SETD2 loss in renal cell carcinoma generates peptides from aberrantly translated retained introns

作者：Marya Kozinova, Alexander L. Metz, Robert G. Uzzo, Janusz Franco‐Barraza, Michael J. Slifker, Jessica Peskin, Ángel Fernández Sanromán, Samra Turajlic, Edna Cukierman, Phillip Phillip Abbosh · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/1538-7445.am2023-6794 · 研究领域：RNA modifications and cancer、Ferroptosis and cancer prognosis

Abstract Introduction: SETD2, a histone H3-K36 trimethyltransferase, is necessary for regulation of proper intron splicing. SETD2 is frequently inactivated in kidney cancer. We hypothesized that SETD2 deficiency would cause aberrant translation of retained introns (ATaRI) that could serve as potential immunotherapeutic targets in SETD2-mutant states. Methods and Results: We detected increased presence of retained introns in SETD2-mutant vs WT tumors in two publicly available renal cell carcinoma RNA-seq data sets. We hypothesized that if intronic sequences translated into proteins, accumulation of misfolded proteins would activate the Unfolded Protein Response (UPR). The UPR pathway was strongly transcriptionally enriched as measured by GSEA, as were several immunotherapy-relevant pathways, suggesting that tumors are inflamed, possibly related to the antigenic nature of translated introns. To investigate this further, we generated Setd2-isogenic mouse renal cancer cells using CRISPR in the RENCA cell line. RNAseq followed by GSEA confirmed upregulation of UPR pathway transcriptional signature in the Setd2-null condition, supporting our observation in human tumors. Indicators of UPR activation such as cleavage of ATF6 and increase in ATF4 and Xbp1 levels in Setd2 deficient vs. unedited RENCA cells, as well as nuclear translocation of ATF6 in SETD2-mutant human kidney cancer samples validates these findings. We then measured the presence of ATaRI-derived peptides in Setd2-mutan...