PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

Lacey, Alexandra; Rodrigues-Hoffman, Aline; Safe, Stephen

doi:10.1158/0008-5472.can-16-1546

Cited by 24 publications

(45 citation statements)

References 48 publications

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“…IL-24 also inhibited migration of ARMS cells (Fig. 4F) and these results were similar to those previously observed in ARMS cells transfected siPAX3-FOXO1 (27,32). Supplemental Figure 2 shows by immunostaining of Rh30 cells after transfection with pCMV-6-IL-24 that a large percentage of the cells expressed IL-24.…”

Section: Resultssupporting

confidence: 90%

“…Studies in this laboratory have reported that NR4A1 is also overexpressed in RMS tumors compared to normal muscle tissue (27) and NR4A1 regulated many of the same genes/pathways observed in other solid tumors (16,19,20,27–32). The NR4A1 ligand 1,1-bis(3-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) which acts as a receptor antagonist inhibits growth, survival, and migration of RMS cells and also inhibits the NR4A1-regulated PAX3-FOXO1 oncogene and RMS tumor growth in a xenograft mouse model (27,32). The present study was initiated after analysis of RNASeq data showed that knockdown of NR4A1 or PAX3-FOXO1 or treatment with the NR4A1 antagonist DIM-C-pPHOH resulted in a 2- to 27.9-fold induction of the tumor suppressor-like factor interleukin-24 (IL-24).…”

Section: Introductionmentioning

confidence: 90%

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Interleukin-24 (IL24) Is Suppressed by PAX3-FOXO1 and Is a Novel Therapy for Rhabdomyosarcoma

Lacey

Hedrick

Cheng

et al. 2018

Molecular Cancer Therapeutics

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Alveolar rhabdomyosarcoma (ARMS) patients have a poor prognosis, and this is primarily due to overexpression of the oncogenic fusion protein PAX3-FOXO1. Results of RNA-sequencing studies show that PAX3-FOXO1 represses expression of interleukin-24 (IL24), and these two genes are inversely expressed in patient tumors. PAX3-FOXO1 also regulates histone deacetylase 5 (HDAC5) in ARMS cells, and results of RNA interference studies confirmed that PAX3-FOXO1-mediated repression of IL24 is HDAC5-dependent. Knockdown of PAX3-FOXO1 decreases ARMS cell proliferation, survival, and migration, and we also observed similar responses in cells after overexpression of IL24, consistent with results reported for this tumor suppressor-like cytokine in other solid tumors. We also observed in double knockdown studies that the inhibition of ARMS cell proliferation, survival, and migration after knockdown of PAX3-FOXO1 was significantly (>75%) reversed by knockdown of IL24. Adenoviral-expressed IL24 was directly injected into ARMS tumors in athymic nude mice, and this resulted in decreased tumor growth and weight. Because adenoviral IL24 has already successfully undergone phase I in clinical trials, this represents an alternative approach (alone and/or combination) for treating ARMS patients who currently undergo cytotoxic drug therapies.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 90%

Interleukin-24 (IL24) Is Suppressed by PAX3-FOXO1 and Is a Novel Therapy for Rhabdomyosarcoma

Lacey

Hedrick

Cheng

et al. 2018

Molecular Cancer Therapeutics

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“…3C). Previous studies showed that Sp TFs regulate expression of the PAX3-FOXO1 gene in Rh30 cells (13,35). In this study, CF 3 DODA-Me decreased expression of PAX3-FOXO1 in this cell line and this was accompanied by downregulation of PAX3-FOXO1-regulated gene products including NMyc, RASSF4, MyoD1, Gremlin, and DAPK1 ( Fig.…”

Section: Resultssupporting

confidence: 59%

Reactive Oxygen Species (ROS)-Inducing Triterpenoid Inhibits Rhabdomyosarcoma Cell and Tumor Growth through Targeting Sp Transcription Factors

Kasiappan

Jutooru

Mohankumar

et al. 2019

Molecular Cancer Research

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Methyl 2-trifluoromethyl-3,11-dioxo-18b-olean-1,12dien-3-oate (CF 3 DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 rhabdomyosarcoma (RMS) cells. CF 3 DODA-Me also inhibited growth and invasion and induced apoptosis in RMS cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF 3 DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 cells). The mechanism of CF 3 DODA-Me-induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The cell and tumor growth effects of CF 3 DODA-Me further emphasize the sensitivity of RMS cells to ROS inducers and their potential clinical applications for treating this deadly disease.Implications: CF 3 DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating rhabdomyosarcoma.

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“…Integrin gene promoters are GC-rich, and α6-, α5-, and β4-integrins are regulated by Nur77/Sp1/Sp3/Sp4/p300 complexes ( 51 ). Binding of the Nur77/Sp4 complex to a GC-rich promoter can enhance the transcription of paired box 3 (PAX3)-forkhead box O1 (FOXO1A); furthermore, the expression of Nur77 regulates β1-integrin which, together with PAX3-FOXO1A, contributes to the migration of tumor cells ( 52 ). These effects may be exploited for the development of novel antitumor drugs.…”

Section: Genomic and Non-genomic Functions Of The Orphan Receptor Nurmentioning

confidence: 99%

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

Chen

2018

Mol Med Report

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Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77/TR3/NGFIB), a member of the nuclear receptor superfamily, is expressed as an early response gene to regulate the expression of multiple target genes. Nur77 has the typical structure of a nuclear receptor, including an N-terminal domain, a DNA binding domain, and a ligand-binding domain. The expression and localization of Nur77 are closely associated with its roles in cell proliferation and apoptosis. Nur77 was first identified as an orphan receptor, the endogenous ligand of which has not yet been identified; however, an increasing number of compounds targeting Nur77 have been reported to have beneficial effects in the treatment of cancer and other diseases. This review provides a brief overview of the identification, structure, expression and localization, transcriptional role and non-genomic function of Nur77, and summarizes the ligands that have been shown to interact with Nur77, including cytosporone B, cisplatin, TMPA, PDNPA, CCE9, THPN, Z-ligustilide, celastrol and bisindole methane compounds, which may potentially be used to treat cancer in humans.

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PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

Cited by 24 publications

References 48 publications

Interleukin-24 (IL24) Is Suppressed by PAX3-FOXO1 and Is a Novel Therapy for Rhabdomyosarcoma

Interleukin-24 (IL24) Is Suppressed by PAX3-FOXO1 and Is a Novel Therapy for Rhabdomyosarcoma

Reactive Oxygen Species (ROS)-Inducing Triterpenoid Inhibits Rhabdomyosarcoma Cell and Tumor Growth through Targeting Sp Transcription Factors

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

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