Ko Panseon, Choi Jee-Hye, Song Seongeun, Keum Seula, Jeong Jangho, Hwang Ye Eun, Kim Jung Woong, Rhee Sangmyung
Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
Int J Mol Sci. 2021 Jun 2;22(11):6018. doi: 10.3390/ijms22116018.
During aggressive cancer progression, cancer cells adapt to unique microenvironments by withstanding various cellular stresses, including endoplasmic reticulum (ER) stress. However, the mechanism whereby cancer cells overcome the ER stress to survive remains to be elucidated. Herein, we demonstrated that microtubule acetylation in cancer cells grown on a stiff matrix promotes cancer progression by preventing excessive ER stress. Downregulation of microtubule acetylation using shRNA or CRSIPR/Cas9 techniques targeting , which encodes α-tubulin N-acetyltransferase (αTAT1), resulted in the upregulation of ER stress markers, changes in ER morphology, and enhanced tunicamycin-induced UPR signaling in cancer cells. A set of genes involved in cancer progression, especially focal adhesion genes, were downregulated in both -knockout and tunicamycin-treated cells, whereas overexpression restored the gene expression inhibited by tunicamycin. Finally, the expression of and ER stress marker genes were negatively correlated in various breast cancer types. Taken together, our results suggest that disruption of microtubule acetylation is a potent therapeutic tool for preventing breast cancer progression through the upregulation of ER stress. Moreover, and ER stress marker genes may be useful diagnostic markers in various breast cancer types.
在侵袭性癌症进展过程中，癌细胞通过耐受包括内质网（ER）应激在内的各种细胞应激来适应独特的微环境。然而，癌细胞克服ER应激以存活的机制仍有待阐明。在此，我们证明在坚硬基质上生长的癌细胞中的微管乙酰化通过防止过度的ER应激促进癌症进展。使用靶向编码α-微管蛋白N-乙酰转移酶（αTAT1）的shRNA或CRSIPR/Cas9技术下调微管乙酰化，导致癌细胞中ER应激标志物上调、ER形态改变以及衣霉素诱导的未折叠蛋白反应（UPR）信号增强。一组参与癌症进展的基因，尤其是粘着斑基因，在αTAT1敲除细胞和衣霉素处理的细胞中均下调，而αTAT1过表达恢复了被衣霉素抑制的基因表达。最后，在各种乳腺癌类型中，αTAT1和ER应激标志物基因的表达呈负相关。综上所述，我们的结果表明，微管乙酰化的破坏是一种通过上调ER应激来预防乳腺癌进展的有效治疗工具。此外，αTAT1和ER应激标志物基因可能是各种乳腺癌类型中有用的诊断标志物。
