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FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma
- Source :
- Oncogene
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
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.
- 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
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 40
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....786b6ffe7846f3f7958f2a15c9922e77