Molecular mechanisms of Guadecitabine induced FGFR4 down regulation in alveolar rhabdomyosarcomas.

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.

• Authors: Emad Darvishi, Katherine Slemmons, Zesheng Wan, Sheetal Mitra, Xiaogang Hou, Jean Hugues Parmentier, Yong-Hwee Eddie Loh, Lee J Helman
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 22 Issue 7 Pg. 274-282 (07 2020) ISSN: 1476-5586 [Electronic] United States
• PMID: 32464274 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histones
• Nuclear Proteins
• Repressor Proteins
• guadecitabine
• Jumonji Domain-Containing Histone Demethylases
• KDM5B protein, human
• FGFR4 protein, human
• Receptor, Fibroblast Growth Factor, Type 4
• Lysine
• Azacitidine

Topics

• Antineoplastic Agents (pharmacology)
• Azacitidine (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatin Immunoprecipitation Sequencing
• Down-Regulation (drug effects)
• Enhancer Elements, Genetic
• Histones (metabolism)
• Humans
• Jumonji Domain-Containing Histone Demethylases (metabolism)
• Lysine (metabolism)
• Nuclear Proteins (metabolism)
• Receptor, Fibroblast Growth Factor, Type 4 (genetics, metabolism)
• Repressor Proteins (metabolism)
• Rhabdomyosarcoma, Alveolar (drug therapy, genetics, metabolism, pathology)