Pluto Bioinformatics

GSE141577: Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss

Bulk RNA sequencing

von Hippel-Lindau (VHL) is a critical tumor suppres- sor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypox- ia-inducible factor 2a (HIF2a). 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 pro- tein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degra- dation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and in- hibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prog- nosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its onco- genic phenotype. Therefore, the pVHL-SFMBT1- SPHK1 axis serves as a potential therapeutic avenue for ccRCC SOURCE: Jeremy Simon (jeremy_simon@med.unc.edu) - UNC Chapel Hill