Abstract PR007: Von Hippel Lindau (VHL) tumor suppressor regulates m6A-dependent gene expression involved in renal tumorigenesis

Abstract

Abstract Background: Renal cancer is the most common adult genitourinary cancer, of which ~85% is accounted for by the clear cell subtype (ccRCC). In the majority of ccRCC, as a result of VHL loss, HIF2a stabilization is sufficient and necessary for promoting ccRCC tumor growth. However, HIF-2 inhibitors have limited efficacy in cancer therapy, highlighting the importance of identifying additional therapeutic vulnerabilities. N6-Methyladenosine (m6A) is the most abundant internal post-translation modification, and its contribution to cancer evolution has just been appreciated. In renal cancer, previous research showed that m6A may play an important role but the molecular mechanism underlying m6A-regulated ccRCC tumorigenesis and aggression is still obscure. Approach and results: We demonstrate that VHL binds with m6A enzymatic complex proteins and regulates METTL3-METTL14 complex formation. VHL depletion suppresses mRNA m6A modification. By performing m6A RIP-Seq for renal cells with or without VHL coupled with RNA-Seq, we identified a selection of genes that their expression may be regulated by m6A. Specifically, PIK3R3 was identified to be one critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promoted renal cell growth and tumor growth while vice versa. Mechanistically, the VHL-m6A regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Conclusion: Taken together, we propose a new mechanism by which VHL regulates m6A through modulating METTL3-METTL14 protein complex formation, therefore promoting PIK3R3 mRNA stability and protein level that is critical for regulating ccRCC tumorigenesis. Citation Format: Cheng Zhang, Zhao Zhang, Austin Hepperla, Miaomiao Yu, Jin Zhou, Lianxin Hu, Jun Fang, Qian Liang, Kexin Xu, Liwei Jia, Qing Zhang. Von Hippel Lindau (VHL) tumor suppressor regulates m6A-dependent gene expression involved in renal tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR007.