HOTAIR LncRNA: A novel oncogenic propellant in human cancer

doi:10.1016/j.cca.2019.12.028

Clinica Chimica Acta

Volume 503, April 2020, Pages 1-18

https://doi.org/10.1016/j.cca.2019.12.028 Get rights and content

Highlights

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Long noncoding RNAs modulate various transcriptional programs and miRNA expression.
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LncRNA-HOTAIR and its genetic variants play crucial role in human carcinogenesis.
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Knockdown of HOTAIR suppresses tumor invasion and metastasis.
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Aberrant HOTAIR expression contributes to chemoresistance in various cancers.
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HOTAIR exhibits the potential of reliable biomarker in clinical diagnosis of cancers.

Abstract

Long non-coding RNAs (lncRNAs) are an important novel class of non-coding RNAs having lengths of 200 nucleotides and low expression. The HOX Transcript Antisense Intergenic RNA (HOTAIR) is one of the most extensively studied lncRNAs found dysregulated in human cancer. Although a growing body of evidence suggests a role fo HOTAIR in pathogenesis, disease progression, drug resistance and reduced survival, its mechanism of action remains largely unclear. Recent studies have identified that HOTAIR facilitates protein-protein interaction thereby affecting diverse pathways in cancer such as epigenetic reprogramming, protein stability and signal transduction. HOTAIR has been shown to promote tumor progression by regulating microRNA expression and function. Moreover, several HOTAIR gene variants have recently been identified and found to increase cancer susceptibility. Here we review recent data on the critical role of HOTAIR in human malignancy and its potential mechanism of action. A more comprehensive understanding of this unique lncRNA is critical to elucidating the pro-oncogenic function of HOTAIR its potential application in diagnosis, prognosis and treatment.

Introduction

Cancer, being a complex and heterogeneous disease, is one of the leading causes of mortality worldwide. Genomic instability functions as a ‘facilitating characteristic’ that initiates tumor formation and is also found to be associated with poor prognosis in cancer patients [1]. Genome sequencing projects revealed that while about 98% of the human genome is non-coding, roughly 85% of it is still transcribed. This results in the generation of a large population of non-coding transcripts; hence, inferring the diverse roles of the transcripts remains to be explored [2]. Advancements in technology and recent discoveries have helped in understanding the functions of these non-coding transcripts, which was previously assumed as a product of leaky transcription, i.e., transcriptional noise [3].

The non-coding DNA of the human genome is known to transcribe various types of noncoding RNAs, such as long non-coding RNAs (lncRNAs) and small non-coding RNAs (sncRNAs), categorized based on their transcript size. The ncRNAs that play a pivotal role in epigenetics include microRNA (miRNA), small interfering RNA (siRNA), PIWI-interacting RNA (piRNA) and lncRNA. LncRNAs can form complex secondary structures and are known to interact with DNA binding proteins to regulate the target gene expression. LncRNAs are found to be master regulators of diverse biological regulatory activities such as gene expression, dosage compensation, allelic imprinting, and genome packaging [4]. The pre-genomic era has delineated the existence and functions of some lncRNAs, such as XIST, TSIX (a lncRNA antisense to XIST), and H19. Since then, large scale genome studies have unearthed the role of various lncRNAs in the vital physiological process as well as in numerous pathological conditions [5]. One of the most extensively investigated lncRNAs-HOTAIR (HOX Transcript Antisense Intergenic RNA), functions as an epigenetic regulator of epidermal tissue development, and shreds of evidence support their involvement in tumor pathogenesis and progression [6], [7]. However, the precise molecular mode of action by which HOTAIR exerts its oncogenic potential remains elusive. Herein, we have reviewed the recent literature to comprehend the mechanism of action and regulation of HOTAIR and its role in human carcinogenesis.

Section snippets

HOTAIR – From genomic junk to the regulator of chromatin dynamics

HOTAIR was first identified by Rinn et al. [8] in the year 2007 using tiling microarray experiments. Human HOTAIR is situated in the HOXC locus of chromosome 12q13.13 flanked in between HOXC11 and HOXC12 loci. HOTAIR is transcribed by RNA polymerase II from the antisense strand, which was confirmed by using strand-specific reverse transcriptase PCR analysis. The 2.2kb long, spliced, polyadenylated and 5′-capped HOTAIR RNA transcript spans around six exons. HOTAIR appears to have a preferential

HOTAIR in breast cancer

Breast cancer (BC) is one of the most common malignancies in women and the second leading cause of cancer mortality among women globally [149]. LncRNAs were found to play a crucial role in the process of tumorigeneses, such as cell proliferation, migration, invasion, radio, and chemoresistance. HOTAIR is widely studied and well-characterized lncRNA that is dysregulated in primary breast tumors and correlates with poor clinical outcome. HOTAIR expression levels in primary tumors were found to be

HOTAIR in hematological malignancies and its clinical relevance

The maintenance of the hematopoietic hierarchy is under the supervisory of various transcriptional regulators. LncRNAs play a pivotal role in regulating different steps of hematopoiesis, including the maintenance of hematopoietic stem cells (HSCs) and their differentiation into myeloid, erythroid, and lymphoid lineages [181], [182], [183].

Role of HOTAIR gene variants in cancer susceptibility

Genome-wide association studies (GWAS) have revealed that most of the single nucleotide polymorphisms (SNP) located within the noncoding region alter the expression and function of lncRNAs, thereby modulating an individual’s cancer risk. Various epidemiological studies have pointed out the role of HOTAIR gene variants to predispose individuals to elevated cancer risk. Interestingly, most of the polymorphisms of HOTAIR are located in the regulatory and intronic regions. However, one SNP

HOTAIR – An exosomal circulating tumor biomarker

Exosomes are extracellular vesicles secreted by various cells such as immune cells as well as tumor cells. Tumor cells are known to secrete more exosomes than healthy cells [219]. Exosomes are present in all types of body fluids such as saliva, urine, and blood. Many studies have highlighted the remarkable upregulation of HOTAIR in cancer tissues compared to normal tissues. Hence, HOTAIR might serve as a potential non-invasive diagnostic and prognostic biomarker for early detection of various

HOTAIR as a potential target for cancer therapy

Among the various genes and proteins that were previously found to be overexpressed or modified in multiple cancers, the HOTAIR lncRNA has attracted much interest owing to its marked and consistent up-regulated expression in almost all cancers. HOTAIR being a natural antisense transcript (NAT), HOTAIR specific single-strand oligonucleotides (antagoNATs) might be efficient in neutralizing the pro-oncogenic potential of HOTAIR, thereby facilitating its degradation using RNase H activity [221].

Discussion and future perspectives

In recent years, there has been significant progress in understanding the role of lncRNAs in various physiological and pathological conditions. Currently, multiple studies have investigated the mechanism of action of crucial lncRNAs. However, additional work needs to be executed to uncover the mysteries of diverse lncRNA functions. Many studies are currently underway to delineate the molecular role of lncRNAs in the pathogenesis of different diseases.

Increasing evidence suggests that the HOTAIR

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

The authors thank SASTRA -Deemed University for providing the necessary facilities.

Funding

The research was supported by Department of Science and Technology (DST) – Science and Engineering Research Board ( SERB), Government of India (Grant no: YSS/2015/001692).

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ReviewHOTAIR LncRNA: A novel oncogenic propellant in human cancer

Highlights

Abstract

Introduction

Section snippets

HOTAIR – From genomic junk to the regulator of chromatin dynamics

HOTAIR in breast cancer

HOTAIR in hematological malignancies and its clinical relevance

Role of HOTAIR gene variants in cancer susceptibility

HOTAIR – An exosomal circulating tumor biomarker

HOTAIR as a potential target for cancer therapy

Discussion and future perspectives

Declaration of Competing Interest

Acknowledgments

Funding

Genom. Proteomics Bioinformatics

Noncoding RNA Res

Trends Cell Biol

Cell

Mol Cell

Mol Cell

Cell

Cell Rep

J Biol Chem

Cell Rep.

Trends Genet

Cell

Can. Cell Int.

Biomed. Pharmacother

Cell

J. Mol. Biol.

Gene

Respir. Med.

Cancer Lett

EBioMedicine

Pharmacol. Ther.

J. Hepatol.

Cancer Treat. Rev.

Mol Cancer

Genomic Instability in cancer: teetering on the limit of tolerance

Can. Res.

Structural and functional differences in the long non-coding RNA HOTAIR in mouse and human

PLoS Genet

HOTAIR: an oncogenic long non-coding RNA in different cancers

Can Biol Med

Long noncoding RNA as modular scaffold of histone modification complexes

Science

Promiscuous RNA binding by Polycomb repressive complex 2

Nat Struct Mol Biol

Molecular architecture of human Polycomb repressive complex 2

Elife

Long noncoding RNAs: Emerging stars in gene regulation, epigenetics and human disease

ChemMedChem

BRCA1 is a negative modulator of the PRC2 complex

EMBO J

Role of Polycomb protein EED in the propagation of repressive histone marks

Nature

Long noncoding RNA HOTAIR involvement in cancer

Tumour Biol

Long non-coding RNAs and chromatin modifiers: their place in the epigenetic code

Epigenetics

Scaffold function of long non- coding RNA HOTAIR in protein ubiquitination

Nat Commun

LncRNA HOTAIR regulates lipopolysaccharide-induced cytokine expression and inflammatory response in macrophages

Sci. Rep.

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

Nature

Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation

PLoS ONE

HOTAIR is dispensible for mouse development

PLoS Genet

Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression

J Int Med Res

HOTAIR in relation to Epithelial-Mesenchymal Transition and cancer stem cells in molecular subtypes of endometrial cancer

Int J Biol Markers

Role of long noncoding RNA HOTAIR in the growth and apoptosis of osteosarcoma cell MG-63

Biomed Res Int

Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-β1 secretion

Mol Cancer

The LncRNA HOTAIR transcription is controlled by HNF4α-induced chromatin

Review
HOTAIR LncRNA: A novel oncogenic propellant in human cancer