Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Abstract

Abstract. Programmed cell death protein 4 (PDCD4) has recently been demonstrated to be implicated in translation and transcription, and the regulation of cell growth. However, the mechanisms underlying PDCD4 function in glioma cells remain to be elucidated. The current study investigated the function and regulation of PDCD4 and the results demonstrated that the expression of PDCD4 was significantly reduced in glioma cells compared with normal cells. When PDCD4 was overexpressed in glioma cells, the proliferation rate and invasive capability of the cells greatly decreased, suggesting that PDCD4 functions as a tumor suppressor in this cell type. In addition, the histone modification status of the PDCD4 gene was analyzed, and chromatin immunoprecipitation assay identified a high density of histone 3 lysine 27 trimethylation on the promoter of PDCD4, which was associated with the long non-coding RNA, homeobox transcript antisense RNA (HOTAIR). The expression of HOTAIR was significantly increased in glioma cells compared with normal cells, and it exerted its function in a polycomb repressive complex 2-dependent manner. These results may provide novel approaches to therapeutically target PDCD4 and HOTAIR in patients with gliomas. IntroductionHuman gliomas are the most prevalent malignant neoplasms of the central nervous system, with an annual incidence of ~5/100,000 worldwide (1). Despite the use of aggressive surgery in combination with chemotherapy, biological therapy and radiotherapy, gliomas continue to be therapeutically challenging (2). For patients with glioblastoma, the relative 5-year survival rate is <5% (3). Novel therapies for the treatment of glioma are warranted; recent advances in the understanding of the molecular and biological nature of this disease may facilitate the development of successful therapeutics (4).PDCD4 protein was initially determined to be overexpressed during apoptosis, which subsequently suppresses tumorigenesis (5,6). Loss of PDCD4 expression is closely associated with the progression of a number of tumors, including glioblastomas (7), and kidney, ovarian and lung cancer (8-10). Low PDCD4 expression levels correlate with poor outcomes in patients with glioblastoma multiforme (11). The frequent loss of PDCD4 in glioblastoma multiforme is partly due to epigenetic silencing secondary to 5' cytosine-phosphate-guanine island methylation (12), in addition to overexpression of microRNA (miRNA)-21, which targets PDCD4 mRNA for degradation (13). Although several studies have examined PDCD4 in glioma, the detailed molecular mechanisms underlying the role of PDCD4 in glioma remain poorly understood.Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides, which are involved in various important events, including transcriptional, epigenetic and post-transcriptional regulation (14,15). A previous study profiled the lncRNA homeobox transcript antisense RNA (HOTAIR), and the results demonstrated that HOTAIR was closely correlated with poor prognosis, molecular ...

Association between expression of HOTAIR and invasiveness of gliomas, and its predictive value

“…Downregulation of HOTAIR can inhibit the proliferation, invasion and migration of tumor cells, and meanwhile promote the apoptosis of glioma cells. 2,19 In our study, the relative expression of HOTAIR was lower in glioma tissues of grade I than in the case of grades II-IV, and multivariate analysis showed that high expression of HOTAIR (>0.40) was an independent risk factor for grades II-IV. These results suggested that HOTAIR was associated with the grades of gliomas and could act as a biomarker reflecting the invasiveness of gliomas.…”

“…As the most common primary tumors in the central nervous system among adults, 1,2 gliomas are classified into 4 grades that reflect the degree of invasiveness/malignancy according to the current 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System. 3 Grade I refers to benign and more circumscribed tumors with low proliferative potential.…”

Identifying Novel Glioma-Associated Noncoding RNAs by Their Expression Profiles

“…lncRNAs can exhibit oncogenic or tumour suppressive functions [ 11 ]. Regarding processes of tumour growth, all three were found to be involved in cell proliferation in glioma [ 39 , 53 – 55 ] and various other cancer types [ 56 – 61 ]. As an oncogenic lncRNA, HOTAIR is involved in epigenetic gene silencing, cell growth, and progression of various cancers [ 42 – 44 ].…”

Long non-coding RNA CASC15 promotes melanoma progression by epigenetically regulating PDCD4

“…CASC15 was previously revealed to be involved in the tumorigenesis of gastric cancer via interacting with EZH2 and WDR5 in nucleus [ 15 ]. PDCD4, a tumor suppressor, was previously proved to be down-regulated by PRC2 complex via increasing the level of H3K27me3 at its promoter in glioma [ 18 ]. Thus, we wondered whether CASC15 could regulate PDCD expression through EZH2 in melanoma.…”