The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

癌症干细胞 (CSC) 中高丰度的药物外排泵有助于化疗耐药。转录调节因子 SMAR1 抑制结直肠癌中的 CSC 扩增，并且 SMAR1 丰度的增加与更好的预后相关。在这里，我们发现在乳腺肿瘤中，通过多能性因子 Oct4 和 Sox2 与组蛋白脱乙酰酶 HDAC1 的协同相互作用，SMAR1在 CSC中的表达降低。通过 SMAR1 依赖性募集 HDAC2 到编码药物外排泵 ABCG2 基因的启动子，过表达 SMAR1 使 CSC 对化疗敏感。用非甾体抗炎药阿司匹林治疗培养的 CSC 或 4T1 荷瘤小鼠可恢复SMAR1表达和ABCG2抑制和增强肿瘤对阿霉素的敏感性。我们的研究结果揭示了调节SMAR1 的转录机制，该机制也调节癌症干性和化学抗性，并表明，通过恢复SMAR1表达，阿司匹林可能会增强干细胞样肿瘤患者的化疗疗效。