Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

Abstract

Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome1, 2, 3 yet their potential involvement in human disease is not well understood4,5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities6,7,8. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

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

“…We initially focused on the promoter of the canonical transcript NR_003716 (HOTAIR‐C) that was first discovered in breast cancer (Gupta et al ., 2010; Rinn et al ., 2007). We examined trimethylation of histone 3 lysine 4 (H3K4me3) that has been used as a marker of the transcriptionally active lncRNA (Guttman et al ., 2009).…”

“…5B). This overlapping implies in sis action of HOTAIR in breast cancer besides its established in trans action via binding to PRC2 (Gupta et al ., 2010; Zhuang et al ., 2015). This notion is appealing because HOXC11 promotes breast cancer and the importance of PRC2 to HOTAIR functions has been challenged recently (McIlroy et al ., 2010; Portoso et al ., 2017).…”

“…The lncRNA genes exhibit tissue‐specific expression patterns and regulate expression of the genes that are pivotal to development and cancer (Cabili et al ., 2011; Guttman et al ., 2009). lncRNA can act as a recruiter and scaffold for assembly of chromatin modifiers on their target genes (Chu et al ., 2011; Gupta et al ., 2010; Spitale et al ., 2011; Tsai et al ., 2010; Wang and Chang, 2011). The lncRNA HOX transcript antisense RNA (HOTAIR) is elevated in breast cancer and promotes metastasis (Gupta et al ., 2010; Rinn et al ., 2007).…”

“…lncRNA can act as a recruiter and scaffold for assembly of chromatin modifiers on their target genes (Chu et al ., 2011; Gupta et al ., 2010; Spitale et al ., 2011; Tsai et al ., 2010; Wang and Chang, 2011). The lncRNA HOX transcript antisense RNA (HOTAIR) is elevated in breast cancer and promotes metastasis (Gupta et al ., 2010; Rinn et al ., 2007). HOTAIR recruits polycomb repressive complex 2 (PCR2) to their target genes for transcriptional repression (Chu et al ., 2011).…”

“…In accordance, an EMT‐like derivative of the human breast cancer MCF‐7 cells exhibited a robust increase in HOTAIR expression and such an increase was required for accelerated proliferation and resistance to cell death (Antoon et al ., 2012; Zhuang et al ., 2015). One intriguing observation in the discovery of HOTAIR in breast cancer is that the RNA levels of HOTAIR in breast cell lines in cell culture are significantly lower than those observed in primary and metastatic breast tumors (Gupta et al ., 2010). This observation implies that conventional 2D culture lacks critical factors that stimulate the expression of HOTAIR.…”