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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157095 | 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 [ChIP-seq]

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.

2022-09-06 | GSE157094 | GEO

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

2022-09-06 | GSE157093 | GEO

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

2022-09-06 | GSE157092 | GEO

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

Project description:Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma

| PRJNA660045 | ENA

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

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

| PRJNA660049 | ENA

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

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

| PRJNA660046 | ENA

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

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

| PRJNA660047 | ENA

KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma.

Project description:Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.

| S-EPMC10894237 | biostudies-literature

Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma.

Project description:Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS.

| S-EPMC6278278 | biostudies-literature

KDM3B inhibitors disrupt PAX3-FOXO1 oncogenic activity in fusion positive rhabdomyosarcoma.

Project description:Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. We screened 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, PFI-63. RNA-seq, ATAC-seq, and docking analyses implicated histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirmed the inhibition of multiple KDMs with highest selectivity for KDM3B. Structural similarity search of PFI-63 identified PFI-90 with improved solubility and potency. Biophysical binding of PFI-90 to KDM3B was demonstrated using NMR and SPR. PFI-90 suppressed the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopied PFI-90 effects. Thus, we report novel KDM inhibitors with highest specificity for KDM3B. Its potent suppression of PAX3-FOXO1 activity can be exploited as a new therapeutic approach for FP-RMS and other transcriptionally driven cancers.

2023-12-31 | GSE219199 | GEO

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