HOTAIR, a cell cycle–associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma

Zhang, Junxia; Han, Lei; Bao, Zhaoshi; Wang, Yingyi; Chen, Luyue; Yan, Wei; Yu, Shizhu; Pu, Peiyu; Liu, Ning; You, Yongping; Jiang, Tao; Kang, Chunsheng

doi:10.1093/neuonc/not131

Cited by 203 publications

(202 citation statements)

References 21 publications

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“…S1C). HOTAIR has been described as an oncogene in several types of cancers, as it promotes metastasis (37); moreover, the increased HOTAIR expression is a biomarker of poor prognosis (38,39). HOTAIR is part of a well-established pathway controlling epigenetic gene silencing whereby the Polycomb Repressing Group (PRC2) is targeted to promoters (40)(41)(42).…”

Section: Resultsmentioning

confidence: 99%

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Pastori

Kapranov

Penas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

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Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumorpromoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.glioblastoma | long noncoding RNAs | epigenetics | BRD4 | I-BET151

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Section: Resultsmentioning

confidence: 99%

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Pastori

Kapranov

Penas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

152

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“…No statistically significant associations were found between the TT and the CC genotypes (p-value = 0.866). Tick marks indicate censored data in cancer, but epidemiological studies evaluating tumor susceptibility conferred by genetic polymorphisms in its locus have not been extensively assessed [18][19][20][21][22]. Indeed, to the best of our knowledge, the current study is the first to evaluate associations between HOTAIR SNPs (rs920778 and rs12826786) and glioma susceptibility and prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Given that HOTAIR expression is a known negative prognostic factor in glioma [19], we evaluated the importance of rs920778 or rs12826786 genotypes in the overall survival of the glioma patients from our dataset. We did not find any associations between rs920778 and rs12826786 and overall survival for GBM patients (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Although HOTAIR expression has been reported as crucial in the carcinogenic process of many cancer types, and its abnormal expression was associated with patient poor prognosis, tumor grade, growth and invasion, and as a putative therapeutic target in glioma [19][20][21], few studies have focused on the significance of SNPs in HOTAIR affecting cancer risk [22][23][24][25][26][27][28]. Critically, no studies have evaluated the impact of HOTAIR SNPs in glioma risk and patient prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Effects of the functional HOTAIR rs920778 and rs12826786 genetic variants in glioma susceptibility and patient prognosis

et al. 2017

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restriction fragment length polymorphism (RFLP). No statistically significant differences were found in the genotype or allele distributions of either rs920778 or rs12826786 between glioma patients and controls, suggesting these SNPs are not associated with glioma risk. No significant associations were found between rs920778 variants and HOTAIR expression levels, while rs12826786 CT genotype was associated with increased intratumoral HOTAIR RNA levels when compared to TT genotype (p-value = 0.04). Univariate (Log-rank) and multivariate (Cox proportional) analyses showed both rs920778 CT and rs12826786 CT genotypes were significantly associated with longer overall survival of WHO grade III anaplastic oligodendroglioma patients. Our results suggest that HOTAIR SNPs rs920778 and rs12826786 do not play a significant role in glioma susceptibility, but may be important prognostic factors in anaplastic oligodendroglioma patients. Future studies are warranted to validate and expand these findings, and to further dissect the importance of these SNPs in glioma.

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“…Several studies have correlated lncRNA expression profiles with different histological subtypes and malignancy grades in gliomas 32, 36, 37. Global gene expression analyses identified 27 lncRNAs that are differentially expressed between astrocytomas and oligodendrogliomas 32.…”

Section: Dysregulated Lncrna Expression In Glioma Pathologymentioning

confidence: 99%

Long non‐coding RNAs in brain tumours: Focus on recent epigenetic findings in glioma

Pop

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Necula

et al. 2018

J Cellular Molecular Medi

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Glioma biology is a major focus in tumour research, primarily due to the aggressiveness and high mortality rate of its most aggressive form, glioblastoma. Progress in understanding the molecular mechanisms behind poor prognosis of glioblastoma, regardless of treatment approaches, has changed the classification of brain tumours after nearly 100 years of relying on anatomopathological criteria. Expanding knowledge in genetic, epigenetic and translational medicine is also beginning to contribute to further elucidating molecular dysregulation in glioma. Long non‐coding RNAs (lncRNAs) and their main representatives, large intergenic non‐coding RNAs (lincRNAs), have recently been under scrutiny in glioma research, revealing novel mechanisms of pathogenesis and reinforcing others. Among those confirmed was the reactivation of events significant for foetal brain development and neuronal commitment. Novel mechanisms of tumour suppression and activation of stem‐like behaviour in tumour cells have also been examined. Interestingly, these processes involve lncRNAs that are present both during normal brain development and in brain malignancies and their reactivation might be explained by epigenetic mechanisms, which we discuss in detail in the present review. In addition, the review discusses the lncRNAs‐induced changes, as well as epigenetic changes that are consequential for tumour formation, affecting, in turn, the expression of various types of lncRNAs.

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HOTAIR, a cell cycle–associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma

Abstract: Our data establish that HOTAIR is an important long noncoding RNA that primarily serves as a prognostic factor for glioma patient survival, as well as a biomarker for identifying glioma molecular subtypes, a critical regulator of cell cycle progression.

Cited by 203 publications

References 21 publications

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Effects of the functional HOTAIR rs920778 and rs12826786 genetic variants in glioma susceptibility and patient prognosis

Long non‐coding RNAs in brain tumours: Focus on recent epigenetic findings in glioma

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