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Mol Oncol. 2017 Dec;11(12):1698-1710. doi: 10.1002/1878-0261.12133. Epub 2017 Oct 30.

Induction of a novel isoform of the lncRNA HOTAIR in Claudin-low breast cancer cells attached to extracellular matrix.

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Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University Spokane, WA, USA.
Department of Sports Medicine and Joint Surgery, The People's Hospital of Liaoning Province, Shenyang, China.
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Department of Pathology, Tulane University School of Medicine, New Orleans, LA, USA.


Elevated overexpression of the lncRNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin-low MDA-MB-231 and Hs578T cells in two-dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin-rich extracellular matrix-based three-dimensional organotypic culture (lrECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin α2 and SRC kinase activity. Moreover, invasive growth was suppressed by HOTAIR-specific siRNA. Induction of HOTAIR in lrECM 3D culture resulted from the activation of a novel isoform of HOTAIR (HOTAIR-N) whose transcription is started from the first intron of the HOXC11 gene. The HOTAIR-N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD4, a reader of transcriptionally active histone markers. Inhibition of BRD4 substantially reduced the expression of HOTAIR in lrECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD4 binding to a novel HOTAIR-N promoter in Claudin-low breast cancer cells that are attached to ECM. Induction of HOTAIR is required for invasive growth of Claudin-low breast cancer cells in lrECM 3D culture.


HOTAIR ; epigenetics; lncRNA; three-dimensional organotypic culture

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