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Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma [ATAC-seq]

ABSTRACT: Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157092 | GEO | 2022/09/06

REPOSITORIES: GEO

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Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma [CUT&RUN]

Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.

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