Curcumin has been shown to suppress the progression of lung cancer, however, the underlying mechanisms are largely unknown. Here, we aimed to investigate the effects of curcumin on the stemness of non‐small cell lung cancer (NSCLC) cells. We found that curcumin reduced the sphere formation ability at the concentrations without affecting the cell viability of NSCLC cells and normal pulmonary epithelial cells, which is evident by the decrease of sphere size and number. In addition, curcumin decreased ALDH activity and the expression of stemness markers (CD133, EpCAM, Oct4). RNA sequencing analysis revealed that the Hippo pathway was mostly enriched in cells with curcumin treatment. Indeed, the expression of cancer stem cell markers was significantly decreased by curcumin treatment by analyzing the RNA sequencing data. Gene set enrichment analysis (GSEA) showed that curcumin negatively regulated the cancer stem cell function and positively modulated cancer stem cell differentiation ability. Furthermore, curcumin enhanced the cisplatin sensitivity of NSCLC cells. Mechanistically, it was found that curcumin promoted the nuclear‐cytoplasm translocation of TAZ, but not YAP, the critical effectors of Hippo pathway. In addition, curcumin destabilzed TAZ protein stability and promoted TAZ protein degradation in lung cancer cells, which is dependent on the proteasome degradation system, not by autophagy lysosome degradation system. Overexpression of TAZ rescued the inhibition of curcumin on the stemness of lung cancer cells. Thus, our results suggest that curcumin can attenuate the stemness of lung cancer cells through promoting TAZ protein degradation and thus activating Hippo pathway.

中文翻译：

---

姜黄素通过促进TAZ的核细胞质易位来抑制非小细胞肺癌的干细胞

姜黄素已显示可抑制肺癌的进展，但是其潜在机制在很大程度上尚不清楚。在这里，我们旨在研究姜黄素对非小细胞肺癌（NSCLC）细胞干性的影响。我们发现，姜黄素在不影响NSCLC细胞和正常肺上皮细胞的细胞活力的情况下，在一定浓度下降低了球的形成能力，这通过球体尺寸和数量的减少可以明显看出。此外，姜黄素降低了ALDH活性和干性标记（CD133，EpCAM，Oct4）的表达。RNA测序分析显示，经过姜黄素处理后，Hippo途径大部分富含细胞。确实，通过分析RNA测序数据，姜黄素治疗显着降低了癌症干细胞标志物的表达。基因集富集分析（GSEA）显示姜黄素负调节癌症干细胞功能，正调节癌症干细胞分化能力。此外，姜黄素增强了NSCLC细胞的顺铂敏感性。从机理上讲，姜黄素可促进TAZ的核质转移，但不能促进Hippo途径的关键效应物YAP。此外，姜黄素破坏了肺癌细胞中TAZ蛋白的稳定性并促进了TAZ蛋白的降解，这取决于蛋白酶体降解系统，而不是自噬溶酶体降解系统。TAZ的过表达拯救了姜黄素对肺癌干细胞的抑制作用。因此，