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FOXP1 drives osteosarcoma development by repressing P21 and RB transcription downstream of P53

Oncogene volume 40, pages 2785–2802 (2021)Cite this article

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Abstract

Osteosarcoma has a poor prognosis, and the poor understanding of the genetic drivers of osteosarcoma hinders further improvement in therapeutic approaches. Transcription factor forkhead box P1 (FOXP1) is a crucial modulator in skeletal development and aging. Here, we determined the role and regulatory mechanisms of FOXP1 in osteosarcoma. Higher FOXP1 expression correlated with malignancy in both osteosarcoma cell lines and clinical biopsies. FOXP1 overexpression and knockdown in osteosarcoma cell lines revealed that FOXP1 promoted proliferation, tumor sphere formation, migration and invasion, and inhibited anoikis. Mechanistically, FOXP1 acted as a repressor of P21 and RB (retinoblastoma protein) transcription, and directly interacted with the tumor suppressor p53 to inhibit its activity. Extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/JNK) signaling and c-JUN/c-FOS transcription factors were found to be upstream activators of FOXP1. Moreover, FOXP1 silencing via lentivirus or adeno-associated virus (AAV)-mediated delivery of shRNA suppressed osteosarcoma development and progression in cell-derived and patient-derived xenograft animal models. Taken together, we demonstrate that FOXP1, which is transactivated by ERK/JNK-c-JUN/c-FOS, drives osteosarcoma development by regulating the p53-P21/RB signaling cascade, suggesting that FOXP1 is a potential target for osteosarcoma therapy.

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Fig. 1: FOXP1 expression correlated with osteosarcoma malignancy.
Fig. 2: FOXP1 overexpression mediated by lentivirus infection enhanced tumorigenic abilities of U2-OS osteosarcoma cells in vitro.
Fig. 3: Knockdown of FOXP1 in osteosarcoma cells inhibited proliferation, stemness, and metastasis properties in vitro.
Fig. 4: FOXP1 influenced p53 signaling pathway, inhibited P21 and RB expression.
Fig. 5: FOXP1 suppressed RB and P21 expression as a transcription repressor.
Fig. 6: FOXP1 interacted with p53 protein in osteosarcoma.
Fig. 7: FOXP1 expression was activated by ERK/JNK-AP-1 signaling axis.
Fig. 8: Silencing of FOXP1 mediated by adeno-associated virus infection restrained osteosarcoma growth in PDX models.

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (81802679), the Shanghai Science and Technology Development Fund (18DZ2291200), and China Postdoctoral Science Foundation (2018M632136 and 2019T120348) to HL.

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  1. Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Hanjun Li, Shengbing Yang & Tingting Tang

  2. Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiuguo Han

  3. Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China

    Yongjie Wang & Yang Dong

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  1. Hanjun Li
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All animal studies were approved by the Animal Ethics Committee of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (HKDL No. 2018–218). All human studies were conducted with the approval of the Independent Ethics Committee of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (No. 2018–80), after receiving written informed consent.

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Li, H., Han, X., Yang, S. et al. FOXP1 drives osteosarcoma development by repressing P21 and RB transcription downstream of P53. Oncogene 40, 2785–2802 (2021). https://doi.org/10.1038/s41388-021-01742-4

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