FTO Promotes Osteosarcoma Progression via YAP and Reduces Cisplatin Sensitivity

Background: Fat mass and obesity-associated protein (FTO), a key demethylase involved in N6-methyladenosine modification, plays significant regulatory roles in various cancers. However, its influence on osteosarcoma progression, sensitivity to the commonly used chemotherapy agent cisplatin, and downstream regulatory mechanisms remain unclear. Methods: Multiple osteosarcoma cell lines were used for expression and drug-sensitivity screening, with MG-63 selected for mechanistic experiments. Genetically modified cell lines were established via viral infection and transfection. In vitro assays, including CCK-8, colony formation, Transwell, wound healing, and flow cytometry, were used to assess cell proliferation, migration, and cisplatin sensitivity. Subcutaneous xenograft and tail vein injection metastasis models were used to evaluate in vivo tumor growth and metastasis. Transcriptome sequencing was performed to identify downstream target genes. Results: Compared to normal osteoblasts, FTO expression was elevated in osteosarcoma cell lines (p < 0.05). Knockdown of FTO inhibited osteosarcoma cell proliferation and migration, reduced tumor growth and metastasis in vivo, and increased sensitivity to cisplatin (all p < 0.01). In contrast, overexpression of FTO produced the opposite effects (all p < 0.05). Yes-associated protein (YAP) was identified as a downstream target of FTO. Overexpression of YAP rescued the tumor-suppressive effects caused by FTO knockdown (all p < 0.01), whereas YAP knockdown attenuated the tumor-promoting functions of FTO overexpression (all p < 0.05). Conclusions: FTO is overexpressed in osteosarcoma, where it promotes tumor progression and reduces cisplatin sensitivity. YAP, as a downstream target of FTO, mediates the oncogenic functions of FTO.