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

Xijuan Liu, Jeremy M. Simon, Haibiao Xie, Lianxin Hu, Jun Wang, Giada Zurlo, Cheng Fan, Travis S. Ptacek, Laura Herring, Xianming Tan, Mingjie Li, Albert S. Baldwin, William Y. Kim, Tao Wu, Marc W. Kirschner, Kan Gong, Qing Zhang

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1294-1306.e5
JournalMolecular cell
Volume77
Issue number6
DOIs
StatePublished - Mar 19 2020

Keywords

  • SFMBT1
  • SPHK1
  • ccRCC
  • pVHL

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Liu, X., Simon, J. M., Xie, H., Hu, L., Wang, J., Zurlo, G., Fan, C., Ptacek, T. S., Herring, L., Tan, X., Li, M., Baldwin, A. S., Kim, W. Y., Wu, T., Kirschner, M. W., Gong, K., & Zhang, Q. (2020). Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss. Molecular cell, 77(6), 1294-1306.e5. https://doi.org/10.1016/j.molcel.2020.01.009