2. Academic Validation
  3. Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss

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.
Xijuan Liu 1,  Jeremy M Simon 2,  Haibiao Xie 3,  Lianxin Hu 4,  Jun Wang 1,  Giada Zurlo 4,  Cheng Fan 1,  Travis S Ptacek 5,  Laura Herring 6,  Xianming Tan 1,  Mingjie Li 4,  Albert S Baldwin 1,  William Y Kim 1,  Tao Wu 7,  Marc W Kirschner 7,  Kan Gong 3,  Qing Zhang 8
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 3 Department of Urology, Peking University First Hospital, Beijing, China.
  • 4 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 6 Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Proteomics Core Facility, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 7 Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
  • 8 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Qing.Zhang@UTSouthwestern.edu.
PMID: 32023483 DOI: 10.1016/j.molcel.2020.01.009
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.

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