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

Mol Cell. 2020 Mar 19;77(6):1294-1306.e5. doi: 10.1016/j.molcel.2020.01.009. Epub 2020 Feb 4.

Abstract

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.

Keywords: SFMBT1; SPHK1; ccRCC; pVHL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology*
  • Cell Cycle
  • Cell Movement
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic*
  • Genome-Wide Association Study
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Prognosis
  • Prolyl Hydroxylases / genetics
  • Prolyl Hydroxylases / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tumor Cells, Cultured
  • Ubiquitination
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Repressor Proteins
  • SFMBT1 protein, human
  • Prolyl Hydroxylases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • VHL protein, human