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FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21Cip1 CDK inhibitor

Oncogene volume 36, pages 850–862 (2017)Cite this article

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Abstract

The role of Forkhead Box F1 (FoxF1) transcription factor in carcinogenesis is not well characterized. Depending on tissue and histological type of cancer, FoxF1 has been shown to be either an oncogene or a tumor suppressor. Alveolar rhabdomyosarcoma (RMS) is the most aggressive pediatric soft-tissue sarcoma. Although FoxF1 is highly expressed in alveolar RMS, the functional role of FoxF1 in RMS is unknown. The present study demonstrates that expression of FoxF1 and its closely related transcription factor FoxF2 are essential for RMS tumor growth. Depletion of FoxF1 or FoxF2 in RMS cells decreased tumor growth in orthotopic mouse models of RMS. The decreased tumorigenesis was associated with reduced tumor cell proliferation. Cell cycle regulatory proteins Cdk2, Cdk4/6, Cyclin D1 and Cyclin E2 were decreased in FoxF1- and FoxF2-deficient RMS tumors. Depletion of either FoxF1 or FoxF2 delayed G1–S cell cycle progression, decreased levels of phosphorylated retinoblastoma protein (Rb) and increased protein levels of the CDK inhibitors, p21Cip1 and p27Kip1. Depletion of both FoxF1 and FoxF2 in tumor cells completely abrogated RMS tumor growth in mice. Overexpression of either FoxF1 or FoxF2 in tumor cells was sufficient to increase tumor growth in orthotopic RMS mouse model. FoxF1 and FoxF2 directly bound to and repressed transcriptional activity of p21Cip1 promoter through −556/−545 bp region, but did not affect p27Kip1 transcription. Knockdown of p21Cip1 restored cell cycle progression in the FoxF1- or FoxF2-deficient tumor cells. Altogether, FoxF1 and FoxF2 promoted RMS tumorigenesis by inducing tumor cell proliferation via transcriptional repression of p21Cip1 gene promoter. Because of the robust oncogenic activity in RMS tumors, FoxF1 and FoxF2 may represent promising targets for anti-tumor therapy.

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Acknowledgements

This work was supported by the Research Grant from the American Cancer Society 125011-RSG-13-325-01-CSM (to TVK), NIH grants R01 CA142724 (to TVK) and R01 HL84151 (to VVK).

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Author notes

  1. D Milewski, A Pradhan and X Wang: These three authors contributed equally to this work.

Authors and Affiliations

  1. Division of Pulmonary Biology, The Perinatal Institute of Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA

    D Milewski, A Pradhan, X Wang, Y Cai, T Le, V V Kalinichenko & T V Kalin

  2. Division of Human Genetics, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA

    X Wang

  3. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA

    B Turpin

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Milewski, D., Pradhan, A., Wang, X. et al. FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21Cip1 CDK inhibitor. Oncogene 36, 850–862 (2017). https://doi.org/10.1038/onc.2016.254

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