FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma

The PAX3-FOXO1 fusion protein is the key oncogenic driver in fusion positive rhabdomyosarcoma (FP-RMS), an aggressive soft tissue malignancy with a particularly poor prognosis. Identifying key downstream targets of PAX3-FOXO1 will provide new therapeutic opportunities for treatment of FP-RMS. Herein...

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Veröffentlicht in:Oncogene 2021-03, Vol.40 (12), p.2182-2199
Hauptverfasser: Milewski, David, Shukla, Samriddhi, Gryder, Berkley E., Pradhan, Arun, Donovan, Johnny, Sudha, Parvathi, Vallabh, Sushmitha, Pyros, Athena, Xu, Yan, Barski, Artem, Szabo, Sara, Turpin, Brian, Pressey, Joseph G., Millay, Douglas P., Khan, Javed, Kalinichenko, Vladimir V., Kalin, Tanya V.
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Sprache:eng
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Zusammenfassung:The PAX3-FOXO1 fusion protein is the key oncogenic driver in fusion positive rhabdomyosarcoma (FP-RMS), an aggressive soft tissue malignancy with a particularly poor prognosis. Identifying key downstream targets of PAX3-FOXO1 will provide new therapeutic opportunities for treatment of FP-RMS. Herein, we demonstrate that Forkhead Box F1 (FOXF1) transcription factor is uniquely expressed in FP-RMS and is required for FP-RMS tumorigenesis. The PAX3-FOXO1 directly binds to FOXF1 enhancers and induces FOXF1 gene expression. CRISPR/Cas9 mediated inactivation of either FOXF1 coding sequence or FOXF1 enhancers suppresses FP-RMS tumorigenesis even in the presence of PAX3-FOXO1 oncogene. Knockdown or genetic knockout of FOXF1 induces myogenic differentiation in PAX3-FOXO1-positive FP-RMS. Over-expression of FOXF1 decreases myogenic differentiation in primary human myoblasts. In FP-RMS tumor cells, FOXF1 protein binds chromatin near enhancers associated with FP-RMS gene signature. FOXF1 cooperates with PAX3-FOXO1 and E-box transcription factors MYOD1 and MYOG to regulate FP-RMS-specific gene expression. Altogether, FOXF1 functions downstream of PAX3-FOXO1 to promote FP-RMS tumorigenesis.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-021-01694-9