The human genome contains non-coding RNAs. Long non-coding RNAs, or lncRNAs, are over 200 nucleotides in length and do not produce proteins. LncRNAs play varied roles in regulating gene expression and influencing cellular processes.
HOX Antisense Intergenic RNA, commonly known as HOTAIR, is a prominent lncRNA. HOTAIR is important in gene regulation, chromatin structure, and human disorders, particularly cancer. Research into HOTAIR’s mechanisms aims to develop new disease treatments.
The Blueprint of HOTAIR
HOTAIR, or HOX Antisense Intergenic RNA, is an lncRNA approximately 2.2 kilobases long, consisting of six exons. It is transcribed by RNA polymerase II, then undergoes splicing and polyadenylation, similar to protein-coding genes.
The gene encoding HOTAIR is located within the HOXC gene cluster on chromosome 12. It is transcribed from the antisense strand of this HOXC gene cluster. While many non-coding RNAs are highly conserved across different species, HOTAIR shows less conservation in evolution, though it is well-conserved among primates, with high sequence identity in chimpanzee and macaque genomes.
Unraveling HOTAIR’s Mechanisms
HOTAIR’s molecular function involves its interaction with and recruitment of chromatin-modifying complexes to specific regions of the genome. A key interaction is with the Polycomb Repressive Complex 2 (PRC2). PRC2 is a histone methyltransferase, and its binding to the 5′-end of HOTAIR, specifically within the first 300 nucleotides, allows HOTAIR to act as a scaffold. This interaction leads to the addition of three methyl groups to lysine 27 of histone H3 (H3K27me3), a modification that typically silences gene expression.
In addition to PRC2, HOTAIR also interacts with Lysine-specific demethylase 1 (LSD1), another epigenetic regulator. The 3′-end of HOTAIR, spanning nucleotides 1500 to 2146, is responsible for binding LSD1. This interaction facilitates the demethylation of histone H3 at lysine 4 (H3K4me2), another epigenetic mark associated with gene repression. By coordinating the recruitment of both PRC2 and LSD1, HOTAIR effectively reconfigures chromatin states, promoting the silencing of target genes, particularly at the HOXD locus on chromosome 2.
HOTAIR’s Role in Disease
HOTAIR’s dysregulation is involved in the progression of numerous cancers. It is frequently found to be overexpressed in several cancer types, contributing to their aggressive characteristics. In breast cancer, for instance, elevated HOTAIR levels are associated with tumor progression and metastasis. Similarly, in liver cancer, gastric cancer, and lung cancer, HOTAIR’s increased expression promotes tumor growth, invasion, and the spread of cancer cells to distant sites.
This lncRNA contributes to cancer development by influencing processes such as cell proliferation, migration, and the epithelial-mesenchymal transition (EMT), which aids in metastasis. Beyond promoting tumor spread, HOTAIR also plays a role in drug resistance, a major challenge in cancer therapy. Its overexpression has been linked to reduced sensitivity of cancer cells to chemotherapy and radiotherapy in various cancers, including small cell lung cancer and colorectal cancer. This involvement makes HOTAIR a potential indicator for predicting treatment response.
Targeting HOTAIR for Treatment
Given HOTAIR’s widespread involvement in cancer progression and drug resistance, it has emerged as a potential target for therapeutic interventions. Current research explores several strategies aimed at modulating HOTAIR expression or interfering with its molecular functions. One promising approach involves the use of antisense oligonucleotides (ASOs). ASOs are designed to bind specifically to HOTAIR RNA, leading to its degradation or inhibiting its activity, thereby reducing its oncogenic effects.
RNA interference (RNAi) technologies, such as small interfering RNAs (siRNAs), are also being investigated to silence HOTAIR expression. These methods aim to block HOTAIR’s ability to recruit chromatin-modifying complexes like PRC2 and LSD1, which in turn could reactivate tumor suppressor genes that HOTAIR typically silences. While these therapeutic strategies are largely in experimental or early developmental stages, they represent a future direction for cancer treatment, offering the potential to overcome drug resistance and inhibit tumor metastasis by specifically targeting this influential lncRNA.