LncRNA DILA1 inhibits Cyclin D1 degradation and contributes to tamoxifen resistance in breast cancer.
LncRNA DILA1 inhibits Cyclin D1 degradation and contributes to tamoxifen resistance in breast cancer.
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LncRNA DILA1 抑制 Cyclin D1 降解并导致乳腺癌中他莫昔芬耐药
DOI：
10.1038/s41467-020-19349-w
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发表时间：
2020-11-02
影响因子：
16.6
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Shi Q;Li Y;Li S;Jin L;Lai H;Wu Y;Cai Z;Zhu M;Li Q;Li Y;Wang J;Liu Y;Wu Z;Song E;Liu Q
细胞周期蛋白D1是推动癌细胞增殖的最重要的癌蛋白之一，与乳腺癌对他莫昔芬的耐药有关。在这里，我们识别了一个lncRNA，DILA1，它与Cyclin D1相互作用，并在对他莫昔芬耐药的乳腺癌细胞中过表达。在机制上，DILA1通过直接与Thr286相互作用并阻止其随后的降解，抑制Thr286处Cyclin D1的磷酸化，导致乳腺癌中Cyclin D1蛋白的过度表达。无论在体内还是体外，敲除DILA1基因都会降低Cyclin D1蛋白的表达，抑制癌细胞的生长，恢复他莫昔芬的敏感性。在接受三苯氧胺治疗的乳腺癌患者中，DILA1的高表达与Cyclin D1蛋白的过度表达和预后不良有关。这项研究表明，之前未被认识到的重要性是，翻译后细胞周期蛋白D1的失调导致了乳腺癌对他莫昔芬的耐药性。揭示了DILA1调节Cyclin D1蛋白稳定性的新机制，提示DILA1是下调Cyclin D1蛋白、逆转三苯氧胺耐药的特异性治疗靶点。细胞周期蛋白D1参与乳腺癌(BC)对他莫昔芬的耐药，但其调控机制尚不清楚。在这里，作者证明了lncRNA DILA1通过与Cyclin D1结合并阻止其降解而导致乳腺癌对他莫昔芬的耐药性。
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. Cyclin D1 is involved in tamoxifen resistance in breast cancer (BC) but how it is regulated is unclear. Here, the authors demonstrate that the LncRNA DILA1 contributes to tamoxifen resistance in breast cancer by binding to Cyclin D1 and preventing its degradation.
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影响因子：
10.5
作者：
Diehl, JA;Zindy, F;Sherr, CJ
通讯作者：
Sherr, CJ
影响因子：
50.3
作者：
Barbash, Olena;Zamfirova, Petia;Lin, Douglas I.;Chen, Xiangmei;Yang, Ke;Nakagawa, Hiroshi;Lu, Fengmin;Rustgi, Anil K.;Diehl, J. Alan
通讯作者：
Diehl, J. Alan
影响因子：
64.8
作者：
通讯作者：
--
长链非编码 RNA 在癌症中的作用、功能和机制。
DOI：
10.1016/j.gpb.2015.09.006
发表时间：
2016-02
期刊：
Genomics, proteomics & bioinformatics
影响因子：
--
作者：
Fang Y;Fullwood MJ
通讯作者：
Fullwood MJ
影响因子：
16.6
作者：
Qu, Le;Wu, Zhenjie;Li, Yaoming;Xu, Zhipeng;Liu, Bing;Liu, Feng;Bao, Yi;Wu, Dengshuang;Liu, Jiayi;Wang, Anbang;Chu, Xiaoyuan;Sun, Yinghao;Chen, Cheng;Zhang, Zhengyu;Wang, Linhui
通讯作者：
Wang, Linhui