HOTAIR beyond repression: In protein degradation, inflammation, DNA damage response, and cell signaling

Abstract

Long noncoding RNAs (lncRNAs) are pervasively transcribed from the mammalian genome as transcripts that are usually >200 nucleotides long. LncRNAs generally do not encode proteins but are involved in a variety of physiological processes, principally as epigenetic regulators. HOX transcript antisense intergenic RNA (HOTAIR) is a well-characterized lncRNA that has been implicated in several cancers and in various other diseases. HOTAIR is a repressor lncRNA and regulates various repressive chromatin modifications. However, recent studies have revealed additional functions of HOTAIR in regulation of protein degradation, microRNA (miRNA) sponging, NF-κB activation, inflammation, immune signaling, and DNA damage response. Herein, we have summarized the diverse functions and modes of action of HOTAIR in protein degradation, inflammation, DNA repair, and diseases, beyond its established functions in gene silencing.

Keywords: Chromatin modification; DNA repair; Gene regulation; HOTAIR; Inflammation; lncRNA.

Figure 1.

HOTAIR recruits and binds PRC2 and LSD1, acting as a transcription-suppressing scaffold. PRC2, bound to the 5’ end of HOTAIR, epigenetically represses gene expression via H3K27me3, while 3’-bound LSD1 does so via H3K4 demethylation.

Figure 2.

Mechanism of competing endogenous (ceRNA) functionality of HOTAIR. HOTAIR contains miRNA response elements (MREs) that can bind to various miRNAs, and can therefore sponge multiple different miRNAs. (B) When HOTAIR is upregulated, more miRNAs are bound by it, freeing the miRNA target genes from miRNA-mediated suppression and resulting in their increased expression.

Figure 3.

HOTAIR modulation of the NF-κB inflammatory pathway in a macrophage. Upon LPS signaling, IκBα is phosphorylated, ubiquitinated, and degraded, releasing NF-κB for translocation into the nucleus. Activated NF-κB binds to promoters of pro-inflammatory cytokines to induce their expression and that of HOTAIR. HOTAIR moves to the cytoplasm, where it facilitates further IκBα degradation so that a positive feedback loop is generated to sustain the pro-inflammatory response.^,

Figure 4.

Top: In human liver cancer stem cells, HOTAIR blocks the recruitment of transcription factor CREB, the coactivator P300, and RNA polymerase II to the SETD2 promoter region, resulting in repressed transcription of this important H3K36 methylator and thus impairing DNA damage response. Bottom: Platinum chemotherapy for ovarian cancer initiates the DDR, leading to activation of NF-κB, which induces HOTAIR. In the platinum-induced DDR reaction, HOTAIR also activates the NF-κB signaling cascade. This results in a positive feedback loop of sustained NF-κB activation and DNA-damage signaling, promoting cellular senescence and chemoresistance.

Figure 5.

Ubiquitination and subsequent proteasomal degradation can be both promoted and suppressed by HOTAIR. Left: HOTAIR interacts with E3 ligases Dzip3 and Mex3b at their RNA-binding domains while also associating with their respective protein substrates, Ataxin-1 and Snurportin-1. The resulting complex formation accelerates the ubiquitination and degradation of these senescence-related proteins. Right: HOTAIR competitively binds to the N-terminal domain (NTD) of androgen receptor (AR) to prevent its interaction with E3 ligase MDM2, blocking AR ubiquitination and proteasomal degradation.