Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss

von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC. [Display omitted] •A genome-wide screen identified SFMBT1 as a pVHL target•Potential Proline hydroxylation of SFMBT1 decreases its protein stability and is regulated by pVHL•SFMBT1 promotes ccRCC tumorigenesis and is upregulated in patients with ccRCC•SFMBT1 increases SPHK1 expression in ccRCC The pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.