The promoting roles of the transcriptional regulator SMAR1 have been revealed in several tumors, such as colorectal and breast cancer, however, its roles in osteosarcoma (OS) progression are still confusing. Here, we find that SMAR1 expression is positively correlated with the overall survival of OS patients and negatively correlated with the expression of stemness markers by analyzing the online datasets. Through analyzing different Gene Expression Omnibus (GEO) datasets, SMAR1 is found to be lowly expressed in OS tissues relative to that in adjacent tissues. Functional experiments indicate that SMAR1 overexpression attenuates the stemness of OS cells, characterized as the decrease of stemness marker expression, sphere‐formation ability and ALDH activity. Mechanistically, it is shown that SMAR1 increases the deacetylation level of the drug efflux pump ABCG2 via recruiting HDAC2 to the promoter of the gene coding ABCG2, and thus decreases ABCG2 transcriptional activity. Additionally, overexpression of ABCG2 rescues the inhibition of SMAR1 overexpression on the stemness of OS cells. Moreover, this SMAR1/ABCG2 axis positively regulates the chemotherapeutic sensitivity of OS cells. This work indicates that SMAR1 is a critical suppressor for OS progression through transcriptionally regulating ABCG2 expression.

中文翻译：

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SMAR1通过抑制ABCG2转录活性减弱骨肉瘤细胞的干性

转录调节因子SMAR1的促进作用已经在几种肿瘤中发现，例如结直肠癌和乳腺癌，但是，其在骨肉瘤（OS）进展中的作用仍然令人困惑。在这里，我们通过分析在线数据集发现，SMAR1表达与OS患者的整体生存呈正相关，与茎标记的表达呈负相关。通过分析不同的基因表达综合（GEO）数据集，发现SMAR1在OS组织中的表达相对于在相邻组织中的表达低。功能实验表明，SMAR1的过表达减弱了OS细胞的干性，其特征是干性标志物表达，球形形成能力和ALDH活性降低。机械上，结果表明，SMAR1通过将HDAC2募集到编码ABCG2的基因的启动子上而增加了药物外排泵ABCG2的脱乙酰基水平，从而降低了ABCG2的转录活性。此外，ABCG2的过表达可以挽救SMAR1的过表达对OS细胞干细胞的抑制作用。此外，此SMAR1 / ABCG2轴可正向调节OS细胞的化学治疗敏感性。这项工作表明，SMAR1是转录调控ABCG2表达的OS进程的关键抑制器。该SMAR1 / ABCG2轴正向调节OS细胞的化学治疗敏感性。这项工作表明，SMAR1是转录调控ABCG2表达的OS进程的关键抑制器。该SMAR1 / ABCG2轴正向调节OS细胞的化学治疗敏感性。这项工作表明，SMAR1是转录调控ABCG2表达的OS进程的关键抑制器。