可逆转乳腺癌对他莫昔芬耐药的新靶点

　　细胞周期蛋白D1是最重要的肿瘤蛋白之一，可促进癌细胞增殖和他莫昔芬耐药，不过其关键机制尚不明确。

　　2020年11月2日，英国《自然》旗下《自然通讯》在线发表中国科学院宋尔卫院士、中山大学孙逸仙纪念医院刘强教授等学者的研究报告，发现长链非编码核糖核酸DILA1可抑制细胞周期蛋白D1降解，并促进乳腺癌对他莫昔芬耐药。

　　该研究发现长链非编码核糖核酸DILA1可与细胞周期蛋白D1相互作用，并且过表达于他莫昔芬耐药乳腺癌细胞。

　　机制分析表明，DILA1可直接抑制细胞周期蛋白D1第286位苏氨酸磷酸化，从而阻断细胞周期蛋白D1降解，引起乳腺癌细胞的周期蛋白D1蛋白过表达。

　　体外细胞实验和动物体内实验表明，抑制DILA1编码基因表达，可减少细胞周期蛋白D1表达、抑制癌细胞生长，并恢复他莫昔芬敏感性。

　　对于接受他莫昔芬治疗的乳腺癌患者，DILA1高表达与低表达相比，细胞周期蛋白D1表达水平显著较高，无复发生存和总生存时间显著较短。

　　因此，该研究结果表明，细胞周期蛋白D1编码基因翻译后失调，对于乳腺癌他莫昔芬耐药具有重要意义。此外，DILA1可调节细胞周期蛋白D1稳定性，有望成为逆转他莫昔芬耐药的新靶点。

Nat Commun. 2020 Nov 2. Online ahead of print.

LncRNA DILA1 inhibits Cyclin D1 degradation and contributes to tamoxifen resistance in breast cancer.

Qianfeng Shi, Yudong Li, Shunying Li, Liang Jin, Hongna Lai, Yanqing Wu, Zijie Cai, Mengdi Zhu, Qian Li, Ying Li, Jingru Wang, Yujie Liu, Zongqi Wu, Erwei Song, Qiang Liu.

Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; The First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou, China.

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.

DOI: 10.1038/s41467-020-19349-w