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Overview of the Multifaceted Functions of LncRNA HOTAIR in Glioblastoma

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16 July 2024

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17 July 2024

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Abstract
Glioblastoma is a highly aggressive brain tumor and is considered to be the most common primary one. Recurrence after treatment is a major problem. The recurrence of GBM is related to different cellular mechanisms and molecular signaling. Therapies to prolong survival are not completely effective. Epigenetics and non-coding genetic elements play a crucial role in gliomagenesis. Non-coding RNAs are novel regulatory RNAs that play key roles in different physiological processes such as gene regulation, cell differentiation, and proliferation. Interestingly, some LncRNAs have a tumor suppressor role while others are oncogenic. In this review article, we are going to illustrate the role of a well-known lncRNA HOX transcript antisense intergenic RNA (HOTAIR) in glioma and highlight the possible functions in glioma in both pre-clinical and clinically evident studies.
Keywords: 
HOTAIR
;  
ncRNAs
;  
GBM
;  
high grade glioma
;  
epigenetics
Subject: 
Biology and Life Sciences  -   Neuroscience and Neurology

Introduction

Glioblastoma (GBM) is an aggressive primary brain tumor [1]. Recurrence is a major problem with a survival rate after one year of about 39.7% [2]. The recurrence of GBM is a complex multifactorial process. Most clinical trials failed to promote prolonged survival, the best outcome was reported with the European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) clinical trials in 2005 [3] Epigenetics and non-coding genetic elements are extensively involved in the virulence of this cancer. Many factors contribute to treatment failure such as the heterogeneity of the GBM microenvironment, repository of stem cells with great regenerative potential, and developing resistance to common therapies.
Non-coding RNAs (ncRNAs) are recent classes of RNA molecules that play essential roles in different physiological processes as gene regulation, cell differentiation ,and growth[4]. The non-coding elements represent a big portion of the human genome, however, its main functions are still poorly understood [5,6]. The mechanism through which ncRNA regulates certain biological processes needs to be more elucidated. Non-coding RNA is classified into small and long non-coding RNA according to the nucleotide sequence. Small ncRNAs (20-200 nucleotides) include microRNAs (miRNAs), small nuclear RNAs (snRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs), Piwi-interacting RNAs (piRNAs) [7].
Long non-coding RNAs are composed of more than 200 nucleotides and could control genes that regulate the cell cycle, apoptosis, and cellular growth in various tissues [8]. Mounting research suggests the role of LncRNAs in different cancers including glioma [9]. For example, a lncRNA nuclear enriched abundant transcript 1 (NEAT1) through manipulating miRNA-449b-5p could enhance invasion of GBM cells and inhibit apoptosis [9]. Another lncRNA H19 was found to correlate with glioma grade and control invasiveness [10]. The tumor suppressor candidate 7 (TUSC7), is a LncRNA that suppresses invasion and migration of glioma cells and correlates with prognosis [10,11]. Some LncRNAs could work as tumor suppressor factors while others are oncogenic. In this review article, we are going to highlight the role of a well-known LncRNA HOX transcript antisense intergenic RNA (HOTAIR) in glioma and highlight the possible biological roles in glioma in both pre-clinical and clinically evident studies.
Mechanism of HOTAIR function:
The lncRNA HOX transcript antisense intergenic RNA (HOTAIR) was the first lncRNA to be identified [12]. It is one of the homeobox superfamilies and comprises 2158 nucleotides. It is transcribed from the HOXC locus on chromosome 12q13.13 [13]. Chromatin modifying complex as polycomb-repressive complex 2 (PRC2) is a binding target for HOTAIR [14]. PRC2 complex induces lysine methylation on histone H3. H3K27-methylation is a form of gene silencing and is assisted by histone methyltransferase EZH2 (Enhancer of Zeste homolog 2) [15]. HOTAIR can silence different genes through interaction with histone lysine-specific demethylase (KDM1) [16]. KDM1 can be combined with REST (RE1-Silencing Transcription factor) and CoREST to promote gene silencing [16]. Histone methylation and demethylation is a dynamic epigenetic feature that controls gene regulation. In early embryo life, HOTAIR is expressed in the genital bud, hind limb bud, and posterior trunk [17]. HOTAIR also can regulate the cell cycle proteins, by adjusting the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin D1 [17]. Aberrant HOTAIR expression has been reported in various tumors, and HOTAIR expression has been correlated with growth, progression, recurrence, and poor prognosis by affecting downstream targets [18,19,20].
Molecular Interactions involving HOTAIR in GBM:
HOTAIR has oncogenic potential in different cancers like breast and renal cancer by enhancing cell proliferation, suppressing apoptosis, and promoting cellular invasion [21,22]. We will highlight the potential mechanisms that involve HOTAIR as a preoncogenic candidate in glioma. HOTAIR was found to be highly expressed in glioma compared to normal brain tissues [23]. A certain study showed that HOTAIR knockdown disrupted mouse intracranial GBM model [24]. A group of investigators observed that HOTAIR is highly expressed in both classic and mesenchymal glioma subtypes compared to neural and proneural subtypes [25]. They identified HOTAIR as a marker that correlates for tumor grade and outcome given the fact that low-grade glioma has lower expression levels of HOTAIR compared with high-grade tumors [25]. Different studies investigating the role of HOTAIR in GBM are summarized in Table 1.
Several transcription factors control HOTAIR expression in glioma. HOXA 9 stimulates the expression of HOTAIR in glioma [23]. The upregulation of HOXA9 was associated with abnormaly aggressive behavior [26]. As mentioned before, HOTAIR can induce gene silencing depending on EZH2, meanwhile, HOXA9 is regulated by the PI3K pathway and the inhibition of EZH2-mediated histone methylation creating a loop between HOTAIR and HOXA9 [23,27].
Another study evaluated the role of programmed cell death protein 4 (PDCD4) in the progression of GBM and found that overexpression of PDCD4 in glioma cells down regulated cellular proliferation suggesting that PDCD4 could function as a tumor suppressor [28]. Lower expression levels of PDCD4 are associated with a high level of histone h3 methylation, which is mediated by HOTAIR [28].
Exposure of glioma cells to a BET inhibitor (I-BET151) downregulated the expression of HOTAIR and stopped cell proliferation through cell cycle arrest. Moreover, the upregulation of HOTAIR abolished the anti-cancer effect of I-BET151 on glioma cells. [29]. The role of HOTAIR as a tumor suppressor gene needs further evaluation [30].
HOTAIR can influence cell-cycle related genes in GBM:
LncRNAs can regulate the cell cycle through several ways Figure 2 [31,32]. For example, ANRIL downregulates p15INK4B expression, and MALAT1 controls B-MYB that controls cell cycle progression [33,34]. Downregulating HOTAIR resulted in cell cycle G0/G1 stage arrest [35]. The downregulation of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4, and the enhanced expression of certain cell cycle-related proteins such as p21 and p16 was associated with HOTAIR suppression in LN229 and U87 cells [25]. HOTAIR regulates about 18 genes that form a cell-cycle related mRNA network [24]. HOTAIR controls glioma cell cycle by regulating FoxM1 and AURKB that are involved in mitosis [24]. Several genes such as ASPM, NCAPG, CDC6, CHEK1, CEP55 play a role in gliomagenesis, through their effect on cell cycle progression [36,37,38,39]. In a certain study, HOTAIR affected the expression of some cell-cycle related genes such as CDC6, NCAPG, CENPE, and PLK4 [24]. As mentioned earlier, HOTAIR can induce gene silencing depending on EZH2 through histone methylation[40]. EZH2 inhibition was reported to stop cell cycle progress at the G0/G1 phase of GBM cells which may favor it as a therapeutic target [40].
Prominent Interactions of HOTAIR with micro-RNA in GBM:
LncRNAs can interact with several mRNAs and affect their activities [41]. LncRNAs can compete with micro RNAs displacing them from binding sites and they are termed competing endogenous RNAs (ceRNAs) [42]. In breast cancer, HOTAIR miR-7 relation is a clear example and in gastric cancer, its pro oncogenic effect was through competing with miR-331-3p [42,43].
HOTAIR/miR-326:
A study has shown that the expression of miR-326 is downregulated in glioma tissues [35]. Knocking down HOTAIR resulted in the upregulation of miR-326 which suppressed the expression of fibroblast growth factor 1 (FGF1) Figure 1 in U87 cells impacting cellular proliferation[35].
HOTAIR/miR-15b:
A study found that HOTAIR reduced miR- 15b expression in glioma cells which may have oncogenic potential [44]. miR-15b could upregulate the tumor suppressor gene p53 expression [44]. HOTAIR, miR-15b, and p53 is a closed loop that controls glioma progression.
HOTAIR/miR-125a:
miR-125a-5p was reported to inhibit glioblastoma cell proliferation, and HOTAIR has been demonstrated to reduce miR-125a expression [45,46]. Schisandrin B, a herbal extract, reduced HOTAIR expression and increased miR-125a-5p expression in glioma cell lines by targeting the mammalian target of rapamycin (mTOR) expression [47].
HOTAIR/miR-219:
miR-219-5p acts as a glioma suppressor by targeting tyrosine kinase and EGFR [48]. HOTAIR has been also shown to inhibit miR-219 in U87 cells, resulting in enhanced cell proliferation and increased cyclin D1 levels [49].
HOTAIR and angiogenesis:
Angiogenesis is controlled by hypoxia mediators; the most well known ones are HIF and VEGF [50,51]. Both HIF and VEGF work together to promote a vascular platform for glioma cells. In nasopharyngeal carcinoma cells, HOTAIR was observed to enhance angiogenesis by activating the transcription promoter of VEGFA [52]. It may act through the formation of extracellular vesicles as it was noticed in the supernatant of GBM culture [53]. Comprehensive studies are needed to evaluate the role of HOTAIR in terms of glioma vascularization.
Potential Use of HOTAIR as a diagnostic marker in GBM:
An absolute need for a non-invasive accurate marker for prognostic implications in patients diagnosed with high-grade gliomas is demanding. The possibility for certain body fluid markers to be used for clinical prediction of glioma is still under investigation. Markers that can monitor response to therapy are essential especially for an aggressive disease like GBM. Differentiating true GBM recurrence from pseudoprogression seems difficult and technically challenging. Conventional MRIs could not easily pick the exact differences between both conditions. A serum biomarker could be a promising tool to aid in the clinical differentiation between both situations.
GFAP, lactate, miR-504, have been reported as potential candidates for diagnosing GBM [54,55,56]. The stability of LncRNAs secondary structures makes them favorable potential biomarkers [57]. HOTAIR also has been identified as a possible serum marker in certain cancers [58,59]. HOTAIR concentration was lower after the surgical treatment of a recurrent GBM and the reduction was more noticeable further weeks after surgery [57]. Further experimental and clinical work should be implemented to evaluate the sensitivity and predictability of HOTAIR as a novel serum biomarker in patients diagnosed with GBM.
HOTAIR as a potential therapeutic target in GBM:
As discussed earlier, HOTAIR can regulate glioma progression in an EZH2-dependent manner through epigenetic role. Therefore, therapeutic targeting of HOTAIR-EZH2 interaction may be utilized as a possible targeting approach. A certain compound AC1Q3QWB that targeted HOTAIR-EZH2, was found to inhibit glioma cell proliferation, with a resultant increase in the tumor suppressor candidate CWF19L1[60,61].
The bromodomain and extraterminal (BET) proteins are epigenetic modulators that have emerged as therapeutic tools for some cancers enriched with epigenetic changes [62]. In a published study, I-BET151 treatment and BRD4 depletion reduced the overexpression of HOTAIR in glioma cells through an effect on transcription and elongation factors [63].
RNAi are possible tools that could be used for inhibiting specific genes, including short interfering RNAs (siRNAs) which are short double-stranded RNAs targeting complementary RNA molecules, resulting in RNA silencing and gene suppression [64]. Carriers of nucleic acids could be used to deliver these siRNAs into the tumor cells. Due to their high stability, iron oxide nanoparticles and specifically SPIONs have been used widely in the delivery [65]. A study has demonstrated the successful delivery of siHOTAIR that subsequently inhibited glioma stem cell proliferation[66]. In a study by Zhang L et al., deleting the HOTAIR regulatory element improved the sensitivity of glioma cells to Temozolomide. [67].
In Temozolomide-resistant GBM cells, HOTAIR was upregulated, while temozolomide resistance was enhanced upon the exosome-mediated transfer of HOTAIR by a mechanism involving miR-519a-3p downregulation [68]. One of the therapeutic challenges is the poor penetration of the blood-brain barrier and achieving a maximal intratumoral concentration. HOTAIR knockdown resulted in improving brain-tumor barrier permeability by a mechanism involving the miR-148b-3p targeting. miR-148b-3p affects the microvascular endothelial cells which control the expression of proteins involved in BBB integrity as ZO-1,claudin-5, and occludin [69].
Table 1. a sample of experimental studies investigating HOTAIR in glioblastoma.
Table 1. a sample of experimental studies investigating HOTAIR in glioblastoma.
Role of HOTAIR Reference

- HOTAIR inhibits the transcription of NLK
in U87 GBM cells, regulate Wnt/β-catenin pathway, inhibit
cell cycle arrest and promote cell migration.

 [70]
- HOTAIR mRNA levels are increased in A172 glioma
cells compared to normal astrocytes.
.		 [71]
- miR-141 directly binds to the 3UTR of HOTAIR in
U251 and U87 glioma cells, inhibiting its expression.		 [72]
- miR-148b-3p downregulates the expression of tight
junction-related proteins including ZO-1, clauidin-5,
and occludin 		[69]
- HOTAIR rs920778 and rs12826786 frequencies
do not differ between glioma patients and controls
 [73]
- HOTAIR levels positively correlate with MMP-7,
MMP-9, and VEGF levels in human glioma 		[74]
- HOTAIR upregulates the expression of hexokinase 2 by
downregulating miR-125		 [75]
- HOTAIR is upregulated in temozolomide-resistant
GBM cells
- Serum exosome HOTAIR levels are higher in GBM
patients’ resistant to temozolomide compared with responders. 		[68]

Conclusions

There is a compelling need for extensive clinical studies uncovering the HOTAIR role in GBM. Therapies to prolong survival in patients diagnosed with GBM are traditional and their effect on survival is not remarkable. More understanding of the biology of HOTAIR will enable researchers to develop new therapeutic strategies and diagnostic markers that will eventually apply in clinical trials.

Credit Author Statement

Conceptualization, Methodology, Validation, Writing - Original Draft, Writing - Review & Editing and Supervision: Dr Azab..

Conflict of Interest

The authors certify that there is no conflict of interest with any financial organization about the material described in the manuscript.

Funding

The authors' did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Preprints 112423 g001
Figure 1. HOTAIR can interact with several other non-coding mRNAs and affect their activities which eventually affect cellular proliferation, apoptosis and cell cycle. MiR-326 inhibition resulted in decreased FGF1 that mediates the activity of the pathway PI3K/AKT/MEK which affects proliferation, migration and apoptosis. MiR-15 inhibition by HOTAIR will affect the level of p53 which is a tumor suppressor gene. Inhibition of miR-148b-3p by HOTAIR results in decreased expression of tight junction proteins which affects the tumor-brain barrier permeability.
Figure 1. HOTAIR can interact with several other non-coding mRNAs and affect their activities which eventually affect cellular proliferation, apoptosis and cell cycle. MiR-326 inhibition resulted in decreased FGF1 that mediates the activity of the pathway PI3K/AKT/MEK which affects proliferation, migration and apoptosis. MiR-15 inhibition by HOTAIR will affect the level of p53 which is a tumor suppressor gene. Inhibition of miR-148b-3p by HOTAIR results in decreased expression of tight junction proteins which affects the tumor-brain barrier permeability.
Preprints 112423 g001
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