P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression

Abstract

Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.

Downregulation of the long non-coding RNA taurine-upregulated gene 1 inhibits glioma cell proliferation and invasion and promotes apoptosis

“…Zhang et al (12) discussed the association between TUG1 expression and NSCLC, revealing that TUG1 expression was downregulated in NSCLC and associated with poor prognosis. TUG1 may be an important factor in the p53-regulatory network; p53 is a tumor suppressor gene, the mutation of which is associated with the occurrence and progression of numerous cancer types, including those of the liver (26), breast (27), bladder (28) and stomach (29).…”

“…Previous studies have demonstrated that TUG1 expression was upregulated in esophageal squamous cell carcinoma (ESCC), potentially promoting the proliferation of ESCC (11), whereas its expression was downregulated in non-small cell lung carcinoma (NSCLC) (12). However, the function of TUG1 in glioma remains unknown.…”

Long non-coding RNA GAS5 inhibits cell proliferation, induces G0/G1 arrest and apoptosis, and functions as a prognostic marker in colorectal cancer

“…transcriptional noise, lncRNAs are now known to participate in the regulation of cellular development, cell growth and the development of human disease, including cancer (16)(17)(18)(19). A number of lncRNAs serve important regulatory roles in chromosome modification (20), transcription in the nucleus and post-transcriptional processing in the cytoplasm (21).…”

Expression and clinicopathological significance of the lncRNA HOXA11-AS in colorectal cancer

“…A recent study of 29 pairs of lung cancer samples indicated that HOXA11-AS expression levels were higher in patients with lymph node metastasis and stage III lung cancer (19), which is inconsistent with the results of the present study. This may be attributed to the small number of samples studied, or may be explained by the notion that the progression of different tumors may be regulated by different expression of the same lncRNA (31,32). Further research is required, however, taken together these results suggest that the function and contribution of HOXA11-AS may be tumor dependent.…”