biostudies-literatureLiu XNational Institute of Neurological Disorders and StrokeNICHD NIH HHSNational Cancer InstituteNCI NIH HHSNINDS NIH HHSCancer Prevention and Research Institute of Texas1294-1306.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC7093231biostudies-literatureUnknown77(6)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.Molecular cellGenome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss.PMC7093231R01 CA068490R21 CA223675P30 CA016086R01 CA211732P30 NS045892U54 HD079124Ptacek TSKim WYWang JHerring LLi MZhang QLiu XZurlo GSimon JMKirschner MWTan XXie HHu LBaldwin ASWu TGong KFan CfalseGenome-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.2020-01-01T00:00:00Z2020 Mar2026-06-02T16:18:40.493Z2025-04-03T21:32:58.784ZS-EPMC70932313202348310.1016/j.molcel.2020.01.009