Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis.
Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis.
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诱导型lncRNA转基因小鼠揭示HOTAIR在促进乳腺癌转移中的持续作用。
DOI：
10.7554/elife.79126
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发表时间：
2022-12-29
期刊：
影响因子：
7.7
通讯作者：
Chang, Howard Y.
中科院分区：
文献类型：
--
作者：
Ma, Qing;Yang, Liuyi;Tolentino, Karen;Wang, Guiping;Zhao, Yang;Litzenburger, Ulrike M.;Shi, Quanming;Zhu, Lin;Yang, Chen;Jiao, Huiyuan;Zhang, Feng;Li, Rui;Tsai, Miao-Chih;Chen, Jun-An;Lai, Ian;Zeng, Hong;Li, Lingjie;Chang, Howard Y.
HOTAIR是一种2.2 kb长的非编码RNA（lncRNA），其调节异常与肿瘤发生、早期发育过程中模式形成的缺陷以及上皮向间质转化（EMT）过程中的不规则性有关。然而，HOTAIR在体内确定的致癌转化及其对染色质动力学的影响还不完全清楚。在这里，我们在MMTV-PyMT乳腺癌易感背景的背景下产生了一种多西环素诱导表达人HOTAIR的转基因小鼠模型，以系统地询问人HOTAIR lncRNA促进乳腺癌进展的细胞机制。我们发现，随着时间的推移，持续高水平的HOTAIR增加了乳腺癌细胞的乳腺转移能力和侵袭力，促进了迁移和随后的肺转移。随后HOTAIR过度表达的撤销恢复了转移表型，表明致癌lncRNA成瘾。此外，HOTAIR过表达改变了多个转移相关基因的细胞转录组和染色质可及性景观，并促进EMT。这些改变在HOTAIR表达恢复到基础水平后的几个细胞周期内被废除，表明可擦除的lncRNA相关的表观遗传记忆。这些结果表明HOTAIR在编程转移基因调控程序中的持续作用。靶向HOTAIR lncRNA可能作为改善乳腺癌进展的治疗策略。
HOTAIR is a 2.2-kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by HOTAIR in vivo and its impact on chromatin dynamics are incompletely understood. Here, we generate a transgenic mouse model with doxycycline-inducible expression of human HOTAIR in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human HOTAIR lncRNA acts to promote breast cancer progression. We show that sustained high levels of HOTAIR over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of HOTAIR overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, HOTAIR overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted EMT. These alterations are abrogated within several cell cycles after HOTAIR expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for HOTAIR in programming a metastatic gene regulatory program. Targeting HOTAIR lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression.
影响因子：
3.7
作者：
Rumney RMH;Coffelt SB;Neale TA;Dhayade S;Tozer GM;Miller G
通讯作者：
Miller G