Homo sapiens Raw sequence reads

The inactivation of von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark characteristic of clear cell renal cell carcinoma (ccRCC). Understanding the pathways affected by VHL loss leading to ccRCC remains challenging. N6-methyladenosine (m6A), the most abundant modification within eukaryotic mRNA, is involved in post-transcriptional regulation of mRNA molecules and has been found to play a significant role in the biological processes of tumorigenesis and cancer progression. Fat mass and obesity-related protein (FTO), an m6A demethylase, is involved in tumor progression and metastasis in several malignancies, but its role in ccRCC is not yet clear. Here, we found that VHL interacts with FTO at the protein level but does not target FTO for ubiquitination and degradation. Instead, VHL acts as an adapter to promote CK2-mediated phosphorylation of FTO, thereby regulating FTO's enzymatic activity. MeRIP-Seq and RNA-seq sequencing analyses identified EGR1 as a target of FTO in VHL-deficient ccRCC cell survival. These findings identify FTO as a potential HIF-independent therapeutic target for treating VHL-deficient ccRCC. Mechanistically, FTO promotes tumorigenesis by suppressing EGR1 expression through m6A modification. In summary, our study highlights the critical role of FTO in ccRCC metastasis. Furthermore, low expression of CK2 in ccRCC is positively correlated with poor prognosis in kidney cancer. These studies suggest FTO and CK2 as potential therapeutic targets in ccRCC.