Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis
- Chinese Academy of Sciences, China
- Stanford University, United States
- Shanghai Jiao Tong University, China
- Academia Sinica, Taiwan
Abstract
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 epithelial to mesenchymal transition. 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.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE201581 and GSE201582.
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Chromatin accessibility analysis of inducible HOTAIR overexpression mouse breast cancer cellsNCBI Gene Expression Omnibus, GSE201581.
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Transcriptome analysis of inducible HOTAIR overexpression mouse breast cancer cellsNCBI Gene Expression Omnibus, GSE201582.
Article and author information
Author details
Funding
National Natural Science Foundation of China (32070870)
- Qing Ma
National Key R&D Program of China (2021YFA1100400)
- Lingjie Li
National Institutes of Health (R35-CA209919)
- Howard Y Chang
Howard Hughes Medical Institute
- Howard Y Chang
National Key R&D Program of China (2022YFA0912900)
- Qing Ma
National Natural Science Foundation of China (32070867)
- Lingjie Li
Guangdong Basic and Applied Basic Research Foundation (2021A1515010758)
- Qing Ma
Guangdong Provincial Key Laboratory of Synthetic Genomics
- Qing Ma
Shenzhen Key Laboratory of Synthetic Genomics (ZDSYS20180206 1806209)
- Qing Ma
Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB18)
- Qing Ma
Program for Oriental Scholars of Shanghai Universities
- Lingjie Li
Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases
- Lingjie Li
Natural Science Foundation of Shanghai (21ZR1435900)
- Lingjie Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All mouse work was performed according to IACUC approved protocols at Stanford University (APLAC-14046). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Copyright
© 2022, Ma et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis
eLife 11:e79126.
https://doi.org/10.7554/eLife.79126
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