The emerging role of the long non-coding RNA HOTAIR in breast cancer development and treatment

Abstract

Despite considering vast majority of the transcribed molecules as merely noise RNA in the last decades, recent advances in the field of molecular biology revealed the mysterious role of long non-coding RNAs (lncRNAs), as a massive part of functional non-protein-coding RNAs. As a crucial lncRNA, HOX antisense intergenic RNA (HOTAIR) has been shown to participate in different processes of normal cell development. Aberrant overexpression of this lncRNA contributes to breast cancer progression, through different molecular mechanisms. In this review, we briefly discuss the structure of HOTAIR in the context of genome and impact of this lncRNA on normal human development. We subsequently summarize the potential role of HOTAIR overexpression on different processes of breast cancer development. Ultimately, the relationship of this lncRNA with different therapeutic approaches is discussed.

Keywords: Breast cancer; HOTAIR; Normal development; Therapeutic approaches; lncRNA.

Fig. 1

Schematic location of HOTAIR. This lincRNA has been located at 12q13.13, between HOXC11 and HOXC12 genes, in the antisense strand. It contains six exons (including two domains in the exon 6). The promoter region of HOTAIR contains different binding factor location, including ER, IRF1 and NF-κB

Fig. 2

Schematic illustration of HOTAIR interactions with PRC2 and LSD1 complexes. To function as scaffold and platform, 5′ end of HOTAIR could epigenetically mediates interaction of PRC2 complex (including EZH2, EED, SUZ1 and different RbAp) and other accompaniment proteins with promoter region of the particular genes. Additionally, appropriate function of LSD1/CoREST/REST complex depends on the interaction with 3′ end of HOTAIR, leading to de-methylation of H3K4me2 at promoter region and suppression of the corresponding gene expression. TSS; transcription start site

Fig. 3

Molecular mechanisms of HOTAIR activity to promote cell proliferation. It is proposed that IRF-1 could negatively regulate HOTAIR expression. Activity of HOTAIR could induce CDK1 and CDK2 activity, leading to phosphorylation of EZH2 in the PRC2. Interaction of HOTAIR and PRC2 causes methylation of STAT3. This subsequently contributes to STAT3 phosphorylation, as activated form of protein, recruiting Cyclin D1. Additionally, could positively regulate HOTAIR activity, by affecting the corresponded gene promoter. Collaboration of Cyclin D1 with CDK4 and CDK6 coordinates in post-translational phosphorylation of some proteins and activity of some necessary transcription factors required for transition of G1 to S cell cycle. Alternatively, activity of HOTAIR could down-regulate p27. Defect of this protein could negatively promote activity of Cyclin D-CDK4 and Cyclin E-CDK2. This consequently promotes cell proliferation by contributing to G1 to S phase transition

Fig. 4

Effect of HOTAIR on epithelial-mesenchymal transition. HOTAIR could promote epithelial-mesenchymal transition (EMT) through at least three pathways. lincRNA HOTAIR activity could indirectly inhibit miR-7. This leads to overexpression of SETDB1, STAT3, c-Myc, twist and miR-9, while E-cadherin is down-regulated. HOTAIR activity could also promote prometastatic activity of cancer cells by regulating VEGF, MMP-9, β-catenin and Vimentin. Moreover, lincRNA HOTAIR could coordinate in tripartite SNAIl/HOTAIR/EZH2 complex. This complex involves in general chromatin modification to inhibit expression of the genes involved in epithelial formation (e.g. HNF4α, HNF1α and E-cadherin)