Experimental and Molecular Pathology 118 (2021) 104578 Available online 22 November 2020 0014-4800/© 2020 Elsevier Inc. All rights reserved. Review HOX transcript antisense RNA: An oncogenic lncRNA in diverse malignancies Soudeh Ghafouri-Fard a , Sepideh Dashti b , Molood Farsi c , Mohammad Taheri d, * a Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran b Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran c Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran d Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran A R T I C L E INFO Keywords: HOTAIR Expression Polymorphism Long non-coding RNA ABSTRACT HOX transcript antisense RNA (HOTAIR) is a transcript produced from the antisense strand of the HOXC gene cluster and infuencing expression of genes from the HOXD locus. HOTAIR has prominent roles in different as- pects of carcinogenic process from cancer initiation to metastasis. A number of in vitro, in vivo and human investigations have confrmed the oncogenic impacts of HOTAIR. The diagnostic power of HOTAIR in dis- tinguishing cancer status from healthy status has been optimal in gastric cancer, pancreatic adenocarcinoma and colorectal cancer. The most important achievement in this regard has been provided by studies that verifed diagnostic value of this lncRNA in the serum samples, potentiating its application in non-invasive diagnosis of cancer. Moreover, HOTAIR has a crucial role in determination of response of cancer cells to therapeutic mo- dalities. The current review aims to explain the outlines of these studies to emphasize its potential as a biomarker and therapeutic target for these conditions. 1. Introduction HOX transcript antisense RNA (HOTAIR) is a transcript which is transcribed from the antisense strand of the HOXC gene cluster (Woo and Kingston, 2007). This transcript is categorized as a long non-coding RNA (lncRNA) (Sayad et al., 2017). Being located on chromosome 12q13.13, this lncRNA has 6 exons in human (He et al., 2011). This lncRNA is regarded as an important modulator of chromatin confgu- ration and organization which has the capacity to bind with polycomb repressive complex 2 (PRC2), thus infuencing PRC2 recruitment on several gene loci (Gupta et al., 2010). Notably, HOTAIR regulates expression of genes via trans mechanisms as its silencing increases transcription of genes from the HOXD locus on chromosome 2 (Bhan and Mandal, 2014) without infuencing expression of the HOXC gene cluster (Rinn et al., 2007). The effects of HOTAIR on gene expression is exerted over 40 kilobases of HOXD region (Rinn et al., 2007). HOTAIR binds PRC2 through its 5 ′ region, while it uses its 3 ′ region for binding with the LSD1/CoREST/REST complex. Therefore, HOTAIR regulates PRC2 and LSD1 occupation on chromatin for the purpose of harmonized histone H3 lysine 27 (H3K27) methylation and lysine 4 demethylation (Tsai et al., 2010). Others have shown a PRC2-independent role for HOTAIR in induction of transcriptional repression. They showed that PRC2 occupation on chromatin might be resulted from gene silencing (Portoso et al., 2017). This lncRNA has been shown to exert its regulatory func- tions on gene expression through modulation of histone marks (Bhan and Mandal, 2014) as well as regulation of microRNA (miRNA)-medi- ated inhibition of gene expression through competitively binding with these small-sized transcripts (Tang and Hann, 2018). Fig. 1 depicts a number of miRNAs which are sponged by HOTAIR and their targets. Compared with humans, this lncRNA is functionally and structurally different in the mice. Hotair deletion in addition to the omission of the HoxC cluster has unexpectedly trivial impacts in mice models, implying rapid evolution of this lncRNA within mammalians (Schorderet and Duboule, 2011). However, another study has shown that deletion of this lncRNA in mice cells results in derepression of several genes, homeotic changes in the spine and deformity of metacarpal-carpal bones. Further studies showed that inactivation of this lncRNA increases H3K4me3 marks and decreases H3K27me3 marks at target genes. Thus, Hotair induces a silent chromatin condition at Hox locus and other loci (Li et al., 2013a). Contrary to this study, Amˆ andio et al. demonstrated no noticeable infuence of Hotair inactivation on Hoxd genes expression in vivo. Moreover, no morphological deformity was detected in knocked * Corresponding author. E-mail address: mohammad_823@yahoo.com (M. Taheri). Contents lists available at ScienceDirect Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp https://doi.org/10.1016/j.yexmp.2020.104578 Received 22 September 2020; Received in revised form 11 October 2020; Accepted 20 November 2020