YTHDF1-mediated translational activation of SETD2 suppresses aerobic glycolysis and sensitizes renal cell carcinoma to sunitinib.
TL;DR
The findings identify the YTHDF1/SETD2/p53 axis as a critical translational-epigenetic-metabolic relay, providing a compelling rationale for leveraging epitranscriptomic machineries to improve therapeutic sensitivity in advanced renal cancer.
Abstract
Renal cell carcinoma (RCC) is a highly aggressive malignancy often characterized by metabolic rewiring and limited long-term responses to targeted therapies. In this study, we unveil a previously uncharacterized tumor-suppressive paradigm driven by the m6A reader YTHDF1. Through multi-omics integration and clinical validation, we demonstrate that YTHDF1 is downregulated in RCC and serves as a clinically relevant biomarker associated with favorable clinicopathological features. Mechanistically, YTHDF1 functions in an m6A-dependent manner to directly promote the translational efficiency of the epigenetic modifier SETD2. SETD2 functions as a transcriptional co-activator for p53, triggering the transactivation of the p53/TIGAR metabolic checkpoint to block aerobic glycolysis. Disruption of the YTHDF1/SETD2/p53 axis induces enhanced glycolysis, which fuels tumor proliferation and metastasis. Importantly, we show that genetic overexpression of YTHDF1 not only restricts RCC aggressiveness but also enhances the therapeutic efficacy of sunitinib both in vitro and in vivo. Collectively, our findings identify the YTHDF1/SETD2/p53 axis as a critical translational-epigenetic-metabolic relay, providing a compelling rationale for leveraging epitranscriptomic machineries to improve therapeutic sensitivity in advanced renal cancer.