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Phase separation-based screening identifies arsenic trioxide as the N-Myc-DNA interaction inhibitor for neuroblastoma therapy

ABSTRACT: Transcription factors (TFs) like N-Myc are crucial in disease including cancer. MYCN amplification is a pivotal biomarker for stratifying high-risk neuroblastoma patients. The difficulty in targeting N-Myc poses a significant challenge for treating high-risk neuroblastoma. Since transcription factors activate transcription by binding to DNA, inhibiting this DNA-binding could disrupt their function and offer a therapeutic approach. Herein, we develop a high-throughput in vivo model to screen for inhibitors of protein-DNA interaction (PDI), utilizing phase separation and DNA-binding properties. Base on this, we identify arsenic trioxide (ATO) as the first N-Myc-DNA interaction inhibitor. ATO directly binds to N-Myc to disrupt its interaction with DNA, thereby destroying its transcriptional activity and reducing the expression of its target genes. Consistently, ATO significantly inhibits the cell proliferation and clone formation ability of MYCN-amplified neuroblastoma cells. More importantly, we used 5 patient-derived neuroblastoma cells to evaluate the therapy clinical value of ATO. Finally, we found ATO synergizes with the chemotherapy drug cisplatin in treating neuroblastoma in vitro and in vivo. Together, we not only construct a PDI inhibitor screening model for transcriptional factor and uncover ATO as the first DNA binding inhibitor of N-Myc, but also identify ATO as a promising therapeutic regimen for MYCN-amplified neuroblastoma, especially in refractory patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279740 | GEO | 2025/03/27

REPOSITORIES: GEO

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Disruption of KLHL37-N-Myc complex restores N-Myc degradation and arrests neuroblastoma growth in mouse models

Project description:MYCN amplification accounts for the most common genetic aberration in neuroblastoma and strongly predicts the aggressive progression and poor clinical prognosis. However, clinically effective therapies that directly target N-Myc activity are limited. N-Myc is a transcription factor, and its stability are tightly controlled by ubiquitination-dependent proteasomal degradation. Here, we discovered that Kelch-like protein 37 (KLHL37) played a crucial role in enhancing the protein stability of N-Myc in neuroblastoma. KLHL37 directly interacted with N-Myc to disrupt the N-Myc/FBXW7 interaction, thereby stabilizing N-Myc and enabling tumor progression. Suppressing KLHL37 effectively induced the degradation of N-Myc and exhibited a profound inhibitory effect on the growth of MYCN-amplified neuroblastoma. Notably, we identified RTA-408 as an inhibitor of KLHL37 to disrupt KLHL37-N-Myc complex, promoting the degradation of N-Myc and suppressing neuroblastoma in vivo and in vitro. Moreover, we elucidated the therapeutic potential of RTA-408 for neuroblastoma by utilizing the PDC and PDX tumor models. RTA408's anti-tumor effects may not be exclusively via KLHL37, and specific KLHL37 inhibitors are expected to be developed in the future. These findings not only uncover the biological function of KLHL37 in regulating N-Myc stability, but also indicate that KLHL37 inhibition is a promising therapeutic regimen for neuroblastoma, especially in MYCN-amplified patients.

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KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [CUT&TAG]

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KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [RNA-seq]

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KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [ATAC-Seq]

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

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

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