The m 6 A RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor

Proc Natl Acad Sci U S A. 2020 Sep 1;117(35):21441-21449. doi: 10.1073/pnas.2000516117. Epub 2020 Aug 19.

Abstract

Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m6A RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHL-deficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIF-deficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide m6A-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma.

Keywords: FTO; SLC1A5; kidney cancer; synthetic lethality; von Hippel–Lindau.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
  • Amino Acid Transport System ASC / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Cell Line, Tumor
  • Computer Simulation
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Mice, Knockout
  • Minor Histocompatibility Antigens / metabolism
  • Synthetic Lethal Mutations*
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*

Substances

  • Amino Acid Transport System ASC
  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • Minor Histocompatibility Antigens
  • SLC1A5 protein, human
  • endothelial PAS domain-containing protein 1
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human