A naturally derived small molecule PSM0537 targets the AF1Q-TCF4 interaction to suppress COX2 expression and inhibit cell proliferation and metastasis in osteosarcoma.

ALL1 fused gene from chromosome 1q (AF1Q) functions as an oncogene in several types of cancers, but it has not been observed in osteosarcoma. In this study, we revealed that AF1Q was overexpressed in multiple osteosarcoma cell lines, and its expression level increased with the severity of tumor malignancy in osteosarcoma biopsies. AF1Q was coupled with the transcription factor T cell factor 4 (TCF4) to assemble a complex to bind to the promoter of cyclooxygenase 2 () and activate its expression. The individual knockdown of , or in osteosarcoma cell lines significantly decreased cell proliferation and invasion . The tumor xenograft model also indicated that the individual knockdown of , or could inhibit tumor growth and metastasis. On the basis of these promising results, we established an AlphaScreen method to identify the compounds that disrupted the AF1Q-TCF4 interaction in a naturally derived small molecule pool. We discovered a compound called PSM0537, which showed a strong ability to inhibit the AF1Q-TCF4 interaction at a low dose of half-maximal inhibitory concentration (IC) (210.3 ± 15.6 nM). The administration of PSM0537 and could dramatically inhibit cell proliferation, invasion, and metastasis. Collectively, our findings reveal that the AF1Q-TCF4 transcriptional complex controls the expression of and that targeting the AF1Q-TCF4 interaction with PSM0537 could inhibit tumor cell growth and metastasis. Our results provide a new path for chemotherapy of osteosarcoma.