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

Abstract

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.

Prognostic and clinicopathological significance of long noncoding RNA HOXA11-AS expression in human solid tumors: a meta-analysis

“…In gastric cancer, lncRNA H19 promotes cell proliferation and inhibits cell apoptosis [ 34 ]. Li et al [ 35 ] showed that LncRNA HOTAIR enhanced invasion and metastasis of breast cancer. Moreover, lncRNA HOXA11-AS has been found to induce tumor progression and stemness maintenance in cervical cancer [ 14 ].…”

Changes in long non-coding RNA expression profiles related to the antagonistic effects of Escherichia coli F17 on lamb spleens

“…Due to the rapid development of transcriptome analysis, lncRNAs have recently been considered as a novel modulator of cell development 14 . The lncRNAs that we have identified in this study are mainly associated with cancer, such as prostate cancer 15 , gastric cancer 16 , lung cancer 17 and breast cancer 18 , as well as reproduction 19 – 22 . However, investigations of lamb diarrhoea in relation to lncRNAs are limited.…”

Cancer‑related long noncoding RNAs show aberrant expression profiles and competing endogenous RNA potential in esophageal adenocarcinoma

“…HOTAIR is a highly studied lncRNA. Previous studies demonstrated that it serves a role in the development and progression of various types of solid tumor, including renal cell carcinoma, colorectal cancer, breast cancer, gastric cancer, non-small cell lung cancer, cervical cancer and ovarian epithelial carcinoma (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). In addition, Ren et al (46) demonstrated that HOTAIR can control the cell cycle by acting as a competing endogenous 'sponge' to downregulate miR-1 and upregulate cyclin D1 in ESCC.…”