143 - Selenoprotein loss resulting from Alkbh8 deficiency engages senescence and metabolic programming and predicts poor clear cell renal cancer cell survival

Abstract

Over 14,000 Americans die each year from kidney cancer with clear cell Renal Cell Carcinoma (ccRCC) being the most prevalent and malignant type. Disruptions in glutathione (GSH) metabolism have emerged as predictors of poor survival in ccRCC. Critically important to the maintenance of the GSH redox cycle are the activities of many selenocysteine-containing GSH metabolizing enzymes whose translation is controlled by the tRNA methyltransferase alkylation repair homolog 8 (Alkbh8). Epitransciptomic marks, in the form of tRNA modifications, can regulate gene expression at the level of translation. Our studies indicate that defective epitranscriptomic regulation and impairment in selenocysteine (SEC) incorporation, resulting from a deficiency in tRNA methytransferase Alkbh8 (Alkbh8-/-), alters glutathione (GSH) metabolism (4) and triggers a gene signature that is highly predictive (Hazard Ratio 2.65, p