2. Academic Validation
  3. Molecular mechanisms of Guadecitabine induced FGFR4 down regulation in alveolar rhabdomyosarcomas

Molecular mechanisms of Guadecitabine induced FGFR4 down regulation in alveolar rhabdomyosarcomas

  • Neoplasia. 2020 Jul;22(7):274-282. doi: 10.1016/j.neo.2020.05.001.
Emad Darvishi 1,  Katherine Slemmons 1,  Zesheng Wan 1,  Sheetal Mitra 1,  Xiaogang Hou 1,  Jean Hugues Parmentier 1,  Yong-Hwee Eddie Loh 2,  Lee J Helman 3
Affiliations

Affiliations

  • 1 Division of Hematology-Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  • 2 USC Libraries Bioinformatics Services, Los Angeles, CA, USA.
  • 3 Division of Hematology-Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: lhelman@chla.usc.edu.
PMID: 32464274 DOI: 10.1016/j.neo.2020.05.001
Abstract

Fibroblast Growth Factor receptor 4 (FGFR4) aberrant expression and activity have been linked to the pathogenesis of a variety of cancers including rhabdomyosarcomas (RMS). We found that treatment of alveolar rhabdomyosarcoma (aRMS) cells with Guadecitabine (SGI-110), a next-generation DNA Methyltransferase Inhibitor (DNMTi), resulted in a significant reduction of FGFR4 protein levels, 5 days post treatment. Chromatin immunoprecipitation-sequencing (ChIP-seq) in aRMS cells revealed attenuation of the H3K4 mono-methylation across the FGFR4 super enhancer without changes in tri-methylation of either H3K4 or H3K27. These changes were associated with a significant reduction in FGFR4 transcript levels in treated cells. These decreases in H3K4me1 in the FGFR4 super enhancer were also associated with a 240-fold increase in KDM5B (JARID1B) mRNA levels. Immunoblot and immunofluorescent studies also revealed a significant increase in the KDM5B protein levels after treatment in these cells. KDM5B is the only member of KDM5 (JARID1) family of histone lysine demethylases that catalyzes demethylation of H3K4me1. These data together suggest a pleiotropic effect of DNMTi therapy in aRMS cells, converging to significantly lower FGFR4 protein levels in these cells.

Keywords

Alveolar rhabdomyosarcoma (aRMS); Epigenetic marks; Fibroblast growth factor receptor 4 (FGFR4); Guadecitabine (SGI-110); Histone lysine demethylase 5B (KDM5B).

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