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

Abstract

<i>HOTAIR</i> 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 <i>HOTAIR</i> in vivo and its impact on chromatin dynamics are incompletely understood. Here, we generate a transgenic mouse model with doxycycline-inducible expression of human <i>HOTAIR</i> in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human <i>HOTAIR</i> lncRNA acts to promote breast cancer progression. We show that sustained high levels of <i>HOTAIR</i> over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of <i>HOTAIR</i> overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, <i>HOTAIR</i> 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 <i>HOTAIR</i> expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for <i>HOTAIR</i> in programming a metastatic gene regulatory program. Targeting <i>HOTAIR</i> lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression.