Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncogene. 2021 Apr;40(15):2785-2802. doi: 10.1038/s41388-021-01742-4. Epub 2021 Mar 14.
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.
成骨肉瘤预后较差，而对其遗传驱动因素的认识不足，阻碍了治疗方法的进一步改进。叉头框转录因子 P1（FOXP1）是骨骼发育和衰老的关键调节因子。在这里，我们确定了 FOXP1 在成骨肉瘤中的作用和调节机制。FOXP1 表达水平较高与成骨肉瘤细胞系和临床活检的恶性程度相关。FOXP1 在成骨肉瘤细胞系中的过表达和敲低表明，FOXP1 促进增殖、肿瘤球形成、迁移和侵袭，并抑制失巢凋亡。在机制上，FOXP1 作为 P21 和 RB（视网膜母细胞瘤蛋白）转录的抑制剂，直接与肿瘤抑制因子 p53 相互作用，抑制其活性。细胞外信号调节激酶/Jun N 端激酶（ERK/JNK）信号和 c-JUN/c-FOS 转录因子被发现是 FOXP1 的上游激活物。此外，通过慢病毒或腺相关病毒（AAV）介导的 shRNA 沉默 FOXP1，可抑制细胞源性和患者源性异种移植动物模型中成骨肉瘤的发展和进展。综上所述，我们证明了 FOXP1 可被 ERK/JNK-c-JUN/c-FOS 转激活，通过调节 p53-P21/RB 信号级联来驱动成骨肉瘤的发展，提示 FOXP1 可能是成骨肉瘤治疗的潜在靶点。
