A zebrafish chemical suppressor screening identifies small molecule inhibitors of the Wnt/β-catenin pathway

  • Chem Biol. 2014 Apr 24;21(4):530-540. doi: 10.1016/j.chembiol.2014.02.015.
Naoyuki Nishiya  1 ,  Yusuke Oku  2 ,  Yusuke Kumagai  2 ,  Yuki Sato  2 ,  Emi Yamaguchi  2 ,  Akari Sasaki  2 ,  Momoko Shoji  2 ,  Yukimi Ohnishi  2 ,  Hitoshi Okamoto  3 ,  Yoshimasa Uehara  2
Affiliations
  • 1. Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan. Electronic address: [email protected].
  • 2. Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
  • 3. Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
PMID: 24684907 DOI: 10.1016/j.chembiol.2014.02.015
Abstract

Genetic screening for suppressor mutants has been successfully used to identify important signaling regulators. Using an analogy to genetic suppressor screening, we developed a chemical suppressor screening method to identify inhibitors of the Wnt/β-catenin signaling pathway. We used zebrafish embryos in which chemically induced β-catenin accumulation led to an "eyeless" phenotype and conducted a pilot screening for compounds that restored eye development. This approach allowed us to identify geranylgeranyltransferase inhibitor 286 (GGTI-286), a geranylgeranyltransferase (GGTase) inhibitor. Our follow-up studies showed that GGTI-286 reduces nuclear localization of β-catenin and transcription dependent on β-catenin/T cell factor in mammalian cells. In addition to pharmacological inhibition, GGTase gene knockdown also attenuates the nuclear function of β-catenin. Overall, we validate our chemical suppressor screening as a method for identifying Wnt/β-catenin pathway inhibitors and implicate GGTase as a potential therapeutic target for Wnt-activated cancers.

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