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KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma

ABSTRACT: The goal of this study was to define functional and gene regulatory effects of KDM3A and Ets1, and their relationship to the PAX3/FOXO1 driver oncofusion, in fusion-positive Rhabdomyosarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153852 | GEO | 2020/07/07

REPOSITORIES: GEO

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Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma [RNA-Seq]

Project description:Rhabdomyosarcoma (RMS), a malignancy of impaired myogenic differentiation, is the most common soft tissue pediatric cancer. PAX3-FOXO1 oncofusions drive the majority of the clinically more aggressive fusion-positive rhabdomyosarcoma (FP-RMS). Recent studies have established an epigenetic basis for PAX3-FOXO1-driven oncogenic processes. However, details of PAX3-FOXO1 epigenetic mechanisms, including interactions with, and dependence on, other chromatin and transcription factors, are incompletely understood. We previously identified a novel disease-promoting epigenetic axis in RMS, involving the histone demethylase KDM3A and the ETS1 transcription factor, and demonstrated that this epigenetic axis interfaces with PAX3-FOXO1 both phenotypically and transcriptomically, including co-regulation of biological processes and genes important to FP-RMS progression. In this study, we demonstrate that KDM3A and ETS1 colocalize with PAX3-FOXO1 to enhancers of important disease-promoting genes in FP-RMS, including FGF8, IL4R, and MEST, as well as PODXL, which we define herein as a new FP-RMS-promoting gene. We show that ETS1, which is induced by both PAX3-FOXO1 and KDM3A, exists in complex with PAX3-FOXO1, and augments PAX3-FOXO1 chromatin occupancy. We further show that the PAX3-FOXO1/ETS1 complex can be disrupted by the clinically relevant small molecule inhibitor YK-4-279. YK-4-279 displaces PAX3-FOXO1 from chromatin and interferes with PAX3-FOXO1-dependent gene regulation, resulting in potent inhibition of growth and invasive properties in FP-RMS, along with downregulation of FGF8, IL4R, MEST and PODXL expression. We additionally show that, in some FP-RMS, KDM3A also increases PAX3-FOXO1 levels. Together, our studies illuminate mechanisms of action of the KDM3A/ETS1 regulatory module, and reveal novel targetable mechanisms of PAX3-FOXO1 chromatin complex regulation, in FP-RMS.

2024-10-25 | GSE279335 | GEO

Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma [CUT&Run]

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KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma

Project description:KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma

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KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.

Project description:The goal of this study was to understand the function and mechanisms of action of the chromatin factor KDM3A in the pediatric soft tissue cancer Rhabdomyosarcoma

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KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.

Project description:KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.

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PAX3-FOXO1 regulated microRNAs contribute to the pathogenesis of alveolar rhabdomyosarcoma

Project description:Interrogation of microRNA expression and regulation by PAX3-FOXO1 in Fusion-Positive Rhabdomyosarcoma.

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Expression data for analysis of genes affected by PAX3-FOXO1 in alveolar rhabdomyosarcoma cell line Rh4

Project description:PAX3-FOXO1 is a fusion transcription factor characteristic for the majority of alveolar rhabdomyosarcoma tumors. It is the main oncogenic driver and deregulates expression of PAX3 target genes. The PAX3-FOXO1 target gene signature was determined in the Rh4 alveolar rhabdomyosarcoma cell line.

2015-09-29 | GSE73483 | GEO

BioID HEK293T PAX3-FOXO1 proximity labelling

Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.

2021-09-16 | PXD022187 | Pride

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [RNAseq_LHCN_hg19]

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

2022-09-06 | GSE201224 | GEO

KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma.

Project description:Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. RMS exists as two major disease subtypes, oncofusion-negative RMS (FN-RMS) and oncofusion-positive RMS (FP-RMS). FP-RMS is characterized by recurrent PAX3/7-FOXO1 driver oncofusions and is a biologically and clinically aggressive disease. Recent studies have revealed FP-RMS to have a strong epigenetic basis. Epigenetic mechanisms represent potential new therapeutic vulnerabilities in FP-RMS, but their complex details remain to be defined. We previously identified a new disease-promoting epigenetic axis in RMS, involving the chromatin factor KDM3A and the Ets1 transcription factor. In the present study, we define the KDM3A and Ets1 FP-RMS transcriptomes and show that these interface with the recently characterized PAX3/FOXO1-driven gene expression program. KDM3A and Ets1 positively control numerous known and candidate novel PAX3/FOXO1-induced RMS-promoting genes, including subsets under control of PAX3/FOXO1-associated superenhancers (SE), such as MEST. Interestingly, KDM3A and Ets1 also positively control a number of known and candidate novel FP-RMS-promoting, but not PAX3/FOXO1-dependent, genes. Epistatically, Ets1 is downstream of, and exerts disease-promoting effects similar to, both KDM3A and PAX3/FOXO1. MEST also manifests disease-promoting properties in FP-RMS, and KDM3A and Ets1 each impacts activation of the PAX3/FOXO1-associated MEST SE. Taken together, our studies show that the KDM3A/Ets1 epigenetic axis plays an important role in disease promotion in FP-RMS, and provide insight into potential new ways to target aggressive phenotypes in this disease.

| S-EPMC7530783 | biostudies-literature

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