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

Abstract

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.

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Fig. 1: FOXF1 expressed in fusion-positive FP-RMS tumors.
Fig. 2: FOXF1 is a direct transcriptional target of the PAX3-FOXO1 protein.
Fig. 3: FOXF1 is required for PAX3-FOXO1 to drive FP-RMS tumor growth.
Fig. 4: FOXF1 regulates expression of genes critical for FP-RMS tumor growth and metastasis.
Fig. 5: Ectopic expression of FOXF1 in primary human skeletal muscle myoblasts inhibits myogenic differentiation.
Fig. 6: FOXF1 DNA-binding is associated with active enhancers and with binding of PAX3-FOXO1 and myogenic transcription factors.
Fig. 7: FOXF1 binds to enhancers of genes associated with FP-RMS gene signature.
Fig. 8: FOXF1 cooperates with PAX3-FOXO1 and E-box transcription factors to activate the ERRFI1 enhancer.

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Acknowledgements

We thank Tien Le for technical assistance. This work was supported by the NIH grants R01 CA142724 (TVK), R01 HL132849 (TVK), R01 HL141174 (VVK).

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Correspondence to Tanya V. Kalin.

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The work of TVK is supported by NIH (R01CA142724, R01HL132849), the work of VVK is supported by NIH (R01HL141174). AB is a co-founder of Datirium, LLC, the developer of SciDAP data analysis platform. Other authors declare no conflict of interest.

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Milewski, D., Shukla, S., Gryder, B.E. et al. FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma. Oncogene 40, 2182–2199 (2021). https://doi.org/10.1038/s41388-021-01694-9

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