Roles of HOTAIR Long Non-coding RNA in Gliomas and Other CNS Disorders

Abstract

HOX transcript antisense intergenic RNA (HOTAIR) is a long non-coding RNA (lncRNA) which is increasingly being perceived as a tremendous molecular mediator of brain pathophysiology at multiple levels. Epigenetic regulation of target gene expression carried out by HOTAIR is thorough modulation of chromatin modifiers; histone methyltransferase polycomb repressive complex 2 (PRC2) and histone demethylase lysine-specific demethylase 1 (LSD1). Incidentally, HOTAIR was the first lncRNA shown to elicit sponging of specific microRNA (miRNA or miR) species in a trans-acting manner. It has been extensively studied in various cancers, including gliomas and is regarded as a prominent pro-tumorigenic and pro-oncogenic lncRNA. Indeed, the expression of HOTAIR may serve as glioma grade predictor and prognostic biomarker. The objective of this timely review is not only to outline the multifaceted pathogenic roles of HOTAIR in the development and pathophysiology of gliomas and brain cancers, but also to delineate the research findings implicating it as a critical regulator of overall brain pathophysiology. While the major focus is on neuro-oncology, wherein HOTAIR represents a particularly potent underlying pathogenic player and a suitable therapeutic target, mechanisms underlying the regulatory actions of HOTAIR in neurodegeneration, traumatic, hypoxic and ischemic brain injuries, and neuropsychiatric disorders are also presented.

Keywords: Alzheimer’s disease; Brain cancer; Neuropsychiatric diseases; Parkinson’s disease; Sponging; Traumatic brain injury.

Fig. 1

The mechanism of epigenetic regulation mediated by HOTAIR lncRNA. 5′ end of HOTAIR is involved in the binding and regulation of H3K27 trimethylation activity of the polycomb repressive complex 2 (PRC2) via the catalytic subunit EZH2. On the other hand, 3′ end of HOTAIR modulates the H3K4 demethylation activity of lysine-specific demethylase 1 (LSD1)—RE1 silencing transcription factor (REST)—REST corepressor 1 (coREST1)

Fig. 2

HOTAIR as a molecular sponge for miRNAs. HOTAIR acts as a competing endogenous (ceRNA) by binding and inhibiting specific miRNAs, thereby removing the expressional repression of downstream target mRNA transcripts

Fig. 3

HOTAIR in neuronal pathophysiology. Recent studies implicate deregulated HOTAIR signaling in several non-oncological brain disorders