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

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. 8 samples were transfected with two different siRNAs for control, JMJD2B, MYCN and JARID1A.

ORGANISM(S): Homo sapiens

SUBMITTER: JUN YANG

PROVIDER: E-GEOD-45967 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2014-01-01 | E-GEOD-45969 | biostudies-arrayexpress

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

2014-01-01 | GSE45967 | GEO

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

2014-01-01 | GSE45969 | GEO

miR-34 regulates JARID1A expresion (NB1691)

Project description:p53 inactivation occurs only rarely in neuroblastoma, although miR-34, a transcriptional target of p53, is often deleted in neuroblastoma, suggesting another way in which p53 signaling might be impaired. In this study we show that miR-34 directly targets and downregulates the Polycomb Repressive Complex 2 (PRC2) and its associated histone demethylase, JARID1A, in a p53-dependent manner, 8 samples were transfected with siRNA control or JMJD2B, MYCN, JARID1A into NB1691 cells.

2014-01-01 | E-GEOD-49854 | biostudies-arrayexpress

Targeting Myc signaling pathway by inhibition of histone demethylase JMJD2B

Project description:Targeting Myc signaling pathway by inhibition of histone demethylase JMJD2B

| PRJNA196763 | ENA

Homo sapiens

Project description:Targeting Myc signaling pathway by inhibition of histone demethylase JMJD2B (siRNA)

| PRJNA196766 | ENA

Homo sapiens

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

| PRJNA196767 | ENA

miR-34 regulates JARID1A expresion (SK-N-BE2)

Project description:p53 inactivation occurs only rarely in neuroblastoma, although miR-34, a transcriptional target of p53, is often deleted in neuroblastoma, suggesting another way in which p53 signaling might be impaired. In this study we show that miR-34 directly targets and downregulates the Polycomb Repressive Complex 2 (PRC2) and its associated histone demethylase, JARID1A, in a p53-dependent manner, 4 samples were transfected with miRNA control or miR-34a, miR-34b, miR-34c into SK-N-BE2 cells.

2014-01-01 | E-GEOD-49845 | biostudies-arrayexpress

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.

2022-02-17 | PXD029652 | Pride

Identification of JMJD1A and JMJD2B Target Genes in Hypoxic Ovarian Cancer Cells

Project description:The Hypoxia-Inducible Factors induce the expression of the histone demethylases JMJD1A (KDM3A) and JMJD2B (KDM4B), linking the hypoxic tumor microenvironment to epigenetic mechanisms that may foster tumor progression. Using transcript profiling, we have identified genes that are regulated by JMJD1A and JMJD2B in both normoxic and hypoxic conditions in SKOV3ip.1 ovarian cancer cells. This dataset includes expression data obtained from exposing ovarian cancer cells to hypoxia in combination with siRNA-mediated knockdown of the hypoxia-inducible histone demethylases JMJD1A and JMJD2B. These data were used to both identify functional overlap between each histone demethylase, as well as identify effectors of tumor growth mediated by JMJD2B (KDM4B) in normoxia and hypoxia.

2017-03-13 | GSE66894 | GEO

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