Open AccessInduction of a novel isoform of the lnc RNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix
Author(s) -
Li Miao,
Li Xi,
Zhuang Yan,
Flemington Erik K.,
Lin Zhen,
Shan Bin
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12133
Subject(s) - hotair , gene isoform , claudin , extracellular matrix , breast cancer , long non coding rna , extracellular , microbiology and biotechnology , chemistry , rna , biology , cancer research , cancer , gene , tight junction , biochemistry , genetics
Elevated overexpression of the lnc RNA 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 (lr ECM 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 si RNA . Induction of HOTAIR in lr ECM 3D culture resulted from the activation of a novel isoform of HOTAIR ( HOTAIR ‐N) whose transcription is started from the first intron of the HOXC 11 gene. The HOTAIR ‐N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD 4, a reader of transcriptionally active histone markers. Inhibition of BRD 4 substantially reduced the expression of HOTAIR in lr ECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD 4 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 lr ECM 3D culture.