1. Cancer Biology
  2. Chromosomes and Gene Expression

Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis

  1. Qing Ma  Is a corresponding author
  2. Liuyi Yang
  3. Karen Tolentino
  4. Guiping Wang
  5. Yang Zhao
  6. Ulrike M Litzenburger
  7. Quanming Shi
  8. Lin Zhu
  9. Chen Yang
  10. Huiyuan Jiao
  11. Feng Zhang
  12. Rui Li
  13. Miao-Chih Tsai
  14. Jun-An Chen
  15. Ian Lai
  16. Hong Zeng
  17. Lingjie Li  Is a corresponding author
  18. Howard Y Chang  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. Stanford University, United States
  3. Shanghai Jiao Tong University, China
  4. Academia Sinica, Taiwan
https://doi.org/10.7554/eLife.79126
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Cite this article
  1. Qing Ma
  2. Liuyi Yang
  3. Karen Tolentino
  4. Guiping Wang
  5. Yang Zhao
  6. Ulrike M Litzenburger
  7. Quanming Shi
  8. Lin Zhu
  9. Chen Yang
  10. Huiyuan Jiao
  11. Feng Zhang
  12. Rui Li
  13. Miao-Chih Tsai
  14. Jun-An Chen
  15. Ian Lai
  16. Hong Zeng
  17. Lingjie Li
  18. Howard Y Chang
(2022)
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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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.

The following data sets were generated

Article and author information

Author details

  1. Qing Ma

    Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
    For correspondence
    qing.ma@siat.ac.cn
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8361-5275

  2. Liuyi Yang

    Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
    Competing interests
    No competing interests declared.

  3. Karen Tolentino

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  4. Guiping Wang

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  5. Yang Zhao

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  6. Ulrike M Litzenburger

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  7. Quanming Shi

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  8. Lin Zhu

    Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
    Competing interests
    No competing interests declared.

  9. Chen Yang

    Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    No competing interests declared.

  10. Huiyuan Jiao

    Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    No competing interests declared.

  11. Feng Zhang

    Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    No competing interests declared.

  12. Rui Li

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  13. Miao-Chih Tsai

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  14. Jun-An Chen

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9870-3203

  15. Ian Lai

    Stanford Cancer Institute, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8662-7290

  16. Hong Zeng

    Transgenic, Knockout, and Tumor Model Center, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  17. Lingjie Li

    Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    lingjie@shsmu.edu.cn
    Competing interests
    No competing interests declared.

  18. Howard Y Chang

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    For correspondence
    howchang@stanford.edu
    Competing interests
    Howard Y Chang, Reviewing editor, eLifeH.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, and an advisor of 10x Genomics, Arsenal Biosciences, and Spring Discovery..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9459-4393

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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  1. Qing Ma
  2. Liuyi Yang
  3. Karen Tolentino
  4. Guiping Wang
  5. Yang Zhao
  6. Ulrike M Litzenburger
  7. Quanming Shi
  8. Lin Zhu
  9. Chen Yang
  10. Huiyuan Jiao
  11. Feng Zhang
  12. Rui Li
  13. Miao-Chih Tsai
  14. Jun-An Chen
  15. Ian Lai
  16. Hong Zeng
  17. Lingjie Li
  18. Howard Y Chang
(2022)
Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis
eLife 11:e79126.
https://doi.org/10.7554/eLife.79126

Share this article

https://doi.org/10.7554/eLife.79126

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