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

ABSTRACT: 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 (COX2) and activate its expression. The individual knockdown of AF1Q, TCF4, or COX2 in osteosarcoma cell lines significantly decreased cell proliferation and invasion in vitro. The tumor xenograft model also indicated that the individual knockdown of AF1Q, TCF4, or COX2 could inhibit tumor growth and metastasis. On the basis of these promising results, we established an in vitro 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 (IC₅₀) (210.3 ± 15.6 nM). The administration of PSM0537 in vitro and in vivo could dramatically inhibit cell proliferation, invasion, and metastasis. Collectively, our findings reveal that the AF1Q-TCF4 transcriptional complex controls the expression of COX2 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.

SUBMITTER: Duan N

PROVIDER: S-EPMC8263654 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Duan Ning N Zhang Wentao W Song Tao T Li Zhong Z Chen Xun X Ma Wei W

American journal of cancer research 20210615 6

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 (<i>COX2</i>) and activate its ...[more]

PMID: 34249419

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Project description:BackgroundTo investigate the role of microRNA-376b-3p (miR-376b-3p) and regulator of G protein signaling 1 (RGS1) in the proliferation, metastasis, and apoptosis of osteosarcoma.MethodsDifferentially expressed genes (DEGs) between tumor and normal tissues from GSE14359 and GSE33382 in the cancer genome atlas (TCGA) dataset were analyzed with GEO2R online. Similarly, differentially expressed miRNAs from GSE70367 were also analyzed with GEO2R. The interaction between the differentially expressed miRNAs and the shared distal metastasis-related DEGs from the two datasets were analyzed using miRWalk and Cytoscape. RGS1 and miR-376-3p were chosen to verify the prediction. RGS1 stably expressing and silencing cells were established based on the MG63 and U2OS cell lines. The targeting of RGS1 with miR-376b-3p was confirmed with Starbase prediction and luciferase reporter assay. Cell proliferation, metastasis, and apoptosis were characterized in vitro and in xenograft mice.ResultsA total of 10 up-regulated and 8 down-regulated DEGs were characterized as shared metastasis-related DEGs for GSE14359 and GSE33382. Among these DEGs, RGS1 was targeted with miR-376b-3p, a predicted down-regulated miRNA in GSE70367. High expression of RGS1 predicted proliferation, invasion, metastases, and poor prognosis in osteosarcoma. Overexpression of RGS1 promoted proliferation, invasion, mobility, and stemness in MG63 and U2OS cells, while silencing of RGS1 had the opposite effect in both cell lines. High expression of RGS1 promoted tumor growth in xenograft nude mice. RGS1 was targeted with miR-376b-3p; the addition of miR-376b-3p down-regulated RGS1, and suppressed cell proliferation, invasion, and metastasis. Meanwhile, sponging of miR-376b-3p had the opposite effect. The suppressive effects of miR-376b-3p could be abolished with RGS1, as cell proliferation, stemness, metastasis, and invasion were all promoted with RGS1 co-transfection in both cell lines.ConclusionsOur study indicated that RGS1 is a tumor-promoting gene in osteosarcoma, which could be inhibited with miR-376b-3p.

Dataset Information

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

Publications

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

Similar Datasets

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