Epigenetic Regulation of PEPT2 as a Novel Strategy to Improve the Antitumor Efficacy of Lenalidomide in Clear Cell Renal Cell Carcinoma

The poor prognosis of clear cell renal cell carcinoma (ccRCC) is primarily attributed to inherent resistance and malignant progression, yet the underlying mechanism and effective strategies remain poorly understood. Renal drug transporters play an indispensable role in regulating the intracellular concentration of tumor cells. Therefore, this study aims to investigate the role of proton-coupled oligopeptide transporter 2 (PEPT2) in ccRCC. PEPT2 was found to be downregulated in ccRCC tissues and cell lines, and its low expression was associated with an unfavorable prognosis in ccRCC patients. Overexpression of PEPT2 inhibited cell proliferation and metastasis both in vitro and in vivo. Furthermore, the transcriptional repression of PEPT2 was attributed to DNMT3A/B mediated methylation of its promoter, which could be reversed by the epigenetic inhibitor decitabine, leading to the restored expression and functional transport activity of PEPT2. Importantly, the combination treatment with decitabine (an epigenetic inhibitor) and a lenalidomide-dipeptide conjugate (a substrate for PEPT2) significantly enhanced cytotoxicity against ccRCC cells both in vitro and in vivo. Our investigation into the epigenetic repression of PEPT2 promoters has revealed a significant role in the progression of ccRCC. Furthermore, our findings demonstrate that the combination of PEPT2-targeted lenalidomide with epigenetic therapy effectively enhances cytotoxicity in ccRCC cells. This study provides compelling experimental evidence for the potential therapeutic benefit of targeting PEPT2 in the treatment of ccRCC.

DNA methylation; PEPT2; clear cell renal cell carcinoma (ccRCC); drug response; therapeutic targeting.