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Targeting Myc signaling pathway by inhibition of histone demethylase JMJD2B (ciclopirox)

ABSTRACT: Epigenetic alterations appear to modulate Myc signaling. We investigated the role of the histone demethylase JMJD2B in Myc-mediated neuroblastoma pathogenesis. We demonstrate that Myc physically interacts with and recruits this epigenetic modifier, which removes repressive H3K9 methyl marks from Myc-target genes. JMJD2B regulates neuroblastoma proliferation and, together with MYCN amplification, identifies a subgroup of poor prognosis patients. We identify a novel histone demethylase inhibitor, ciclopirox, which targets JMJD2B and, consequently, Myc signaling, thereby inhibiting neuroblastoma proliferation and inducing differentiation. In xenograft studies, genetic and pharmacologic inhibition of JMJD2B resulted in significant tumor growth restriction. Our findings provide insight into epigenetic regulation of Myc via histone methylation and proof-of-concept for pharmacologic inhibition of histone demethylases to target Myc signaling in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45969 | GEO | 2014/01/01

SECONDARY ACCESSION(S): PRJNA196767

REPOSITORIES: GEO

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Targeting Myc signaling pathway by inhibition of histone demethylase JMJD2B (ciclopirox)

Project description:Epigenetic alterations appear to modulate Myc signaling. We investigated the role of the histone demethylase JMJD2B in Myc-mediated neuroblastoma pathogenesis. We demonstrate that Myc physically interacts with and recruits this epigenetic modifier, which removes repressive H3K9 methyl marks from Myc-target genes. JMJD2B regulates neuroblastoma proliferation and, together with MYCN amplification, identifies a subgroup of poor prognosis patients. We identify a novel histone demethylase inhibitor, ciclopirox, which targets JMJD2B and, consequently, Myc signaling, thereby inhibiting neuroblastoma proliferation and inducing differentiation. In xenograft studies, genetic and pharmacologic inhibition of JMJD2B resulted in significant tumor growth restriction. Our findings provide insight into epigenetic regulation of Myc via histone methylation and proof-of-concept for pharmacologic inhibition of histone demethylases to target Myc signaling in cancer. 8 samples were treated with vehicle or ciclopirox.

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