1. FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma
- Author
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Berkley E. Gryder, Joseph G. Pressey, Vladimir V. Kalinichenko, Johnny Donovan, Athena Pyros, Parvathi Sudha, Sushmitha Vallabh, Douglas P. Millay, Sara Szabo, Samriddhi Shukla, Artem Barski, Brian Turpin, Tanya V. Kalin, Javed Khan, David Milewski, Arun Pradhan, and Yan Xu
- Subjects
musculoskeletal diseases ,0301 basic medicine ,Cancer Research ,genetic structures ,Carcinogenesis ,Biology ,Muscle Development ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Rhabdomyosarcoma ,Gene expression ,Genetics ,Humans ,Enhancer ,PAX3 Transcription Factor ,Molecular Biology ,Transcription factor ,MyoD Protein ,Gene knockdown ,Forkhead Box Protein O1 ,Forkhead Transcription Factors ,Gene signature ,musculoskeletal system ,Fusion protein ,Chromatin ,Cell biology ,Fusion-Positive Rhabdomyosarcoma ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,embryonic structures ,Myogenin ,human activities - 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.
- Published
- 2021