Introduction: Five-year survival of metastatic renal cell carcinoma (mRCC) patients is < 10% and African American (AA) males have the highest incidence. In the kidney, Small Solute Carrier (SLC) and Sirtuin (SIRT) gene families regulate redox signaling, oxidative stress responses, transport of glycolysis and Krebs cycle metabolites, etc. We examined the prognostic potential of eleven SLC and SIRT genes to predict clinical outcome in RCC patients and evaluated the biological functions of SLC13A3 in RCC cells.

Methods: Expression of SLC (13A3, 22A6, 47A1, 5A10) and SIRT 1-7 transcript levels was evaluated in a TCGA RCC-dataset (n=604 patients). 13A3 expression was measured by quantitative RT-PCR (qPCR) in matched normal and RCC specimens from 53 patients. Biomarker levels were correlated with clinical outcome, using Mann-Whitney test. RCC cells stably-expressing SLC13A3, were examined for proliferation and cell cycle under normoxia and hypoxia.

Results: In the TCGA dataset, SIRT4, SIRT5, SLC22A6, SLC5A10, and SLC47A1 downregulation and SIRT2, SIRT6 and SIRT7 upregulation correlated with higher tumor-stage and metastasis (P< 0.001). Kaplan-Meier plots showed that these biomarkers stratified patients into low- or high-risk for survival (P<0.001). qPCR showed 40-fold downregulation of SLC13A3 expression in RCC tissues when compared to normal kidney (P< 0.0001). Downregulation was 40-fold in White/Hispanic patients, but 198-fold in AA patients (P=0.0049) and correlated with tumor stage and metastasis (P=0.009). SLC13A3 expression in RCC cells increased GSH transport by 2.5-fold and inhibited cell proliferation by 3-4-fold (P<0.001), due to cell-cycle arrest at G1-S or G2-M checkpoints. Treatment of RCC cells with DNA-demethylating agent 5-Azacytidine and Trichostatin A, induced SLC13A3 expression by 50-fold (P<0.001).

Conclusion: SLC/SIRT family members are potential prognostic biomarkers for RCC. This first study on SLC13A3 reveals that it is a potential tumor suppressor and its downregulation in RCC tissues correlates with metastasis and racial disparity.

Citation Format: Andre R. Jordan, Naureen Mullani, Asif Talukder, Vinata B. Lokeshwar. Small solute carrier and sirtuin genes are potential prognostic biomarkers for renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 587.