LncRNA HOTAIR: A master regulator of chromatin dynamics and cancer

Abstract

Non-coding RNAs (ncRNAs) are emerging classes of regulatory RNA that play key roles in various cellular and physiological processes such as in gene regulation, chromatin dynamics, cell differentiation, and development. NcRNAs are dysregulated in a variety of human disorders including cancers, neurological disorders, and immunological disorders. The mechanisms through which ncRNAs regulate various biological processes and human diseases still remain elusive. HOX antisense intergenic RNA (HOTAIR) is a recently discovered long non-coding RNA (lncRNA) that plays critical role in gene regulation and chromatin dynamics, appears to be misregulated in a variety of cancers. HOTAIR interacts with key epigenetic regulators such as histone methyltransferase PRC2 and histone demethylase LSD1 and regulates gene silencing. Here, we have reviewed recent advancements in understanding the functions and regulation of HOTAIR and its association with cancer and other diseases.

Keywords: Cancer; Epigenetics; HOTAIR; LncRNA; Non-coding RNA.

Figure 1

Genomic location of HOTAIR. HOTAIR (2.2 kb long lncRNA) is transcribed from antisense strand of HOXC gene cluster from 12q13. HOTAIR is flanked by HOXC12 and HOXC11.

Figure 2

Comparison of HOTAIR orthologs in rats, mouse and human. The murine HOTAIR has about 58% and rat HOTAIR has approximately 50% sequence similarity to human HOTAIR. Human HOTAIR is comprised of 6 exons (exon 1, exon 2, exon 3, exon 4, exon 5, and exon 6). Exon1, 3, 4, 5 and 6 are more conserved. Exon2 is absent in the mouse and rat HOTAIR. The exon 6 of rat and mouse has two hypothetical domains: domain A (~235 bp long) and domain B (~239 long). Domain B appears to have more conservation than domain A, in mouse and rats. The extent of sequence conservation is indicated by the darkness of the boxes, darker the color better conserved it is. The numbers on the top indicates the exon numbers

Figure 3

Mechanism of HOTAIR mediated gene silencing. HOTAIR interacts with PRC2 (that contains EZH2, SUZ12, EEDs and RbAp48) and LSD1 complex (that contains CoREST/REST) via its 5’- and 3’-ends, respectively and recruit them to the target gene promoters/loci. EZH2 introduces H3K27-trimethylation and LSD1 demethylates H3K4 and contribute to gene silencing. BRCA1 and HOTAIR, both interact with PRC2. BRCA1 competes with HOTAIR for binding to PRC2. Thus, expression of BRCA1 inhibits the interaction of HOTAIR with PRC2. CDK1/2 phosphorylates T350 residue (in humans and T345 in mouse) of EZH2 that augments the interaction between EZH2 and HOTAIR.

Figure 4

HOTAIR promoter possesses binding sites for various transcription factors. These include estrogen response elements (ERE), Sp1, AP1, HIF transcription factors, NF-κb and others.

Figure 5

Model showing the roles of ERs, MLLs and other ER coregulators during by estradiol, BPA and DES mediated transcriptional regulation of HOTAIR. Estradiol and steroidogenic EDCs such as BPA and DES bind to ERs, ERs get dimerized and get activated. Activated ERs bind to the EREs of the HOTAIR promoter. ER coregulators such as MLL-histone methylases (MLL1, MLL3), CBP/p300 (histone acetyl-transferases) and other ER coregulators are also recruited to the HOTAIR promoter. Promoter histones are methylated at H3K4 via MLLs and acetylated via HATs (CBP/p300), allowing chromatin remodeling and access to the RNAP II to the promoter, ultimately resulting in gene activation.

Figure 6

Regulatory network of HOTAIR. HOTAIR can be induced by estradiol, BPA and DES, Osteopontin, Collagen type-1, NF-κb as well as by other oncoproteins such as c-Myc. On the contrary, miR-141 represses HOTAIR via complementary binding to the HOTAIR and Ago2 mediated degradation of HOTAIR. Epigenetic repression of various genes such as ALPL, BMP2, MMPs, RBM38, p21 etc. by HOTAIR mediated recruitment of PRC2 and LSD1 can regulate various processes such as tumorigenesis, metastasis, Aortic valve calcification drug resistance, cell migration, cell invasion and epithelial to mesenchymal transitions (EMT). HOTAIR also acts a ceRNA and acts as a sink for various miRNAs such as miR-130a, miR-331-3p and miR-124 and modulates various other cellular processes.

Figure 7

Cross-cancer summary of copy number alterations and mutations in HOTAIR based on cBioPortal database [150, 151]