LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer.
LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer.
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作者：
Xue X;Yang YA;Zhang A;Fong KW;Kim J;Song B;Li S;Zhao JC;Yu J
他莫昔芬是一种雌激素受体拮抗剂，是乳腺癌的主要治疗方法，耐药的发展是治愈的主要障碍。尽管HOTAIR等lncrna与乳腺肿瘤发生有关，但它们在化疗耐药中的作用仍然很大程度上未知。在这项研究中，我们报告了HOTAIR在他莫昔芬耐药乳腺癌组织中的表达上调。从机制上讲，HOTAIR是内质网介导的转录抑制的直接靶点，因此通过激素剥夺或他莫昔芬治疗，在内质网信号通路阻断后恢复。有趣的是，HOTAIR的升高增加了内质网蛋白水平，从而增强了内质网在染色质上的占据，并增强了其下游基因调控。即使在缺乏激素的情况下，HOTAIR过表达也足以激活内质网转录程序。在功能上，我们发现HOTAIR过表达会增加乳腺癌细胞的增殖，而其缺失会显著损害细胞存活并消除他莫昔芬耐药细胞的生长。综上所述，lncRNA HOTAIR直接受到ER的抑制，其上调促进了不依赖配体的ER活性，并参与了他莫昔芬耐药。
Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although lncRNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR is up-regulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the lncRNA HOTAIR is directly repressed by ER and its up-regulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.