HOTAIR: a cancer-related long non-coding RNA

Abstract

Long non-coding RNA was dismissed as merely transcriptional "noise" in the past decades. Numerous researches have shown that lncRNAs regulated gene expression at the epigenetic level. Moreover, lncRNAs played important roles in proliferation, apoptosis and invasiveness of tumor cells, and participated in metastatic capacity of cancers. Recent studies revealed HOX transcript antisense RNA, a lncRNA with regulatory functions of transcription, could bind PRC2 and LSD1/CoREST/REST complexes and direct to the specific gene sites, resulted in H3K27 methylation and H3K4 demethylation and ultimately gene silencing. Aberrant HOTAIR expression was associated with various sites of cancers such as breast, hepatocellular, gastric, colorectal, pancreatic et al; and affected survival and prognosis of cancer patients. In this review, we introduce an overall view of HOTAIR by describing the known molecular mechanisms and potential functions of HOTAIR and summarizing the latest progresses on the research of HOTAIR in various human cancers.Key words: HOTAIR, LncRNA, HOX genes, cancer Long non-coding RNAs (LncRNAs) are commonly defined as RNA moleculars larger than 200 nucleotides. LncRNA was first found among transcribed DNA product of the mouse by Okazaki [1]. Many identified lncRNAs were transcribed by RNA polymerase II (RNA pol II) and spliced [2,3]. One view existed in the past few decades that lncRNAs were as diverse as their better known counterpart messenger RNAs (mRNAs), having no protein-coding capacity, were described as transcriptional "noise" [4,5,6]. However, a number of studies have shown that some lncRNAs were involved in embryogenesis and differentiation [7,8]. These lncRNAs are expressed in specific cell types [9, 10, 11] and located in specific subcellular compartments [12,13,14]. Moreover, recent studies have indicated that lncRNAs participated in a wide range of biological pathways and cellular processes. They could regulate gene expression and function, including dosage compensation [15,16] [18,36].HOX transcript antisense RNA (HOTAIR) is a lncRNA which has regulatory functions of transcription and are transcribed from the antisense strand of homeobox C gene locus in chromosome 12. HOTAIR recruits Polycomb Repressive Complex 2 (PRC2) and histone demethylase complex [LSD1 (lysine specific demethylase 1)/CoREST (Co-repressor of RE1-silencing transcription factor)/REST]; then leads to histone H3 tri-methylated at lysine 27 (H3K27me3) and histone H3 dimethyl Lys4 (H3K4me2); consequently results in gene silencing. In addition to its scaffold function to assemble transcription regulators, and a latest study reported that HO-TAIR could also serve as a platform to control protein levels via the ubiquitin-proteasome pathway. HOTAIR facilitated the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b, and then accelerated their degradation. Moreover, HOTAIR levels were highly upregulated in senescent cells. It

Overexpression of long non-coding RNA HOTAIR predicts a poor prognosis in patients with acute myeloid leukemia

“…HOTAIR was first identified as one of 231 lncRNAs that are associated with the human HOX loci, which binds to polycomb repressive complex 2 (PRC2), a transcriptional co-repressor, and recruits it to silence the target genes (18). HOTAIR is also able to interact with a second histone A B modification complex, the LSD1/CoREST/REST complex, which functions by coordinating the targeting of PRC2 and LSD1 to chromatin for methylation of coupled histone H3K27 and demethylation of K4 (24).…”

“…Several recent studies have identified the aberrant expression of HOTAIR in a number of cancer types, including breast, colon, bladder, renal, pancreatic, cervical and lung cancer, and a high level of HOTAIR expression has been correlated with enhanced breast, colon and gastric cancer metastasis. In addition, HOTAIR-knockdown is able to inhibit the invasion and proliferation of cells, as well as altering cell cycle progression and inducing cells apoptosis, thus indicating that HOTAIR may function in the modulation of cancer progression (17)(18)(19).…”

LncRna CPS1-IT1 Suppresses Cell Proliferation, Invasion and Metastasis in Colorectal Cancer

“…To date, a few lncRNAs have been reported to be related to the progression of human cancer [35, 36]. Several lncRNAs have been shown to serve as prognostic and diagnostic markers, such as HOTAIR for brain, breast, and colon cancer [37-40]; MALAT-1 for liver, breast, lung, and prostate cancer [41-43]; OOC1 for colon cancer; and SChLAP1, PCA3, and PCAT-1 for prostate cancer [44, 45]. Moreover, growing evidence has further indicated that lncRNAs functionally act as suppressors of oncogenes.…”

Long noncoding RNAs in hepatocellular carcinoma: Novel insights into their mechanism

“…The 5' domain of HOTAIR can bind to PRC2, while the 3' domain of HOTAIR can bind to the LSD1 (lysine specific demethylase 1)/ CoREST (Co-repressor of RE1-silencing transcription factor)/REST complex; after that, the complexes are targeted and assembled to the HOXD locus; and coordinately regulate histone H3K27 methylation and histone histone 3 methylated at lysine 4 demethylation; consequently, the transcription across 40 kb of the HOXD locus is silenced in trans by DNA methylation [106] . These indicate that the HOTAIR-induced assembly and targeting of LSD1 and PRC2 complexes is a general mechanism for gene silencing across the genome, which plays a vital role in the association with invasion and metastasis in HCC [64] . Expression of HOTAIR is also associated with tumor size and lymph node metastasis in HCC patients [62] .…”