VHL governs m6A modification and PIK3R3 mRNA stability in clear cell renal cell carcinomas
Hyemin Lee, … , Li Zhuang, Boyi Gan
Hyemin Lee, … , Li Zhuang, Boyi Gan
Published April 15, 2024
Citation Information: J Clin Invest. 2024;134(8):e179560. https://doi.org/10.1172/JCI179560.
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Commentary

VHL governs m6A modification and PIK3R3 mRNA stability in clear cell renal cell carcinomas

Abstract

N6-Methyladenosine (m6A), a prevalent posttranscriptional modification, plays an important role in cancer progression. Clear cell renal cell carcinoma (ccRCC) is chiefly associated with the loss of the von Hippel-Lindau (VHL) gene, encoding a component of the E3 ubiquitin ligase complex. In this issue of the JCI, Zhang and colleagues unveiled a function of VHL beyond its canonical role as an E3 ubiquitin ligase in regulating hypoxia-inducible factors (HIFs). It also governed m6A modification by orchestrating the assembly of m6A writer proteins METTL3 and METTL14, thereby stabilizing PIK3R3 mRNA. Mechanistically, PIK3R3 contributed to p85 ubiquitination, which restrained PI3K/AKT signaling and consequently impeded ccRCC growth in cell and mouse models. This discovery provides potential treatment targets in VHL-deficient ccRCCs.

Authors

Hyemin Lee, Li Zhuang, Boyi Gan

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Figure 1

VHL mediates m6A RNA modification in ccRCCs.

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VHL mediates m6A RNA modification in ccRCCs. VHL orchestrates the comple...
VHL orchestrates the complex assembly of METTL3 and METTL14, leading to the incorporation of m6A into PIK3R3 mRNA. The m6A reader proteins, IGF2BP1 and IGF2BP2, play a role in stabilizing PIK3R3 mRNA. The stabilized PIK3R3 mRNA leads to increased levels of PIK3R3 protein, which in turn exert a negative regulatory effect on the p85 protein, consequently inhibiting PI3K/AKT signaling and impeding ccRCC tumorigenesis.