A negative regulation loop of long noncoding RNA HOTAIR and p53 in non-small-cell lung cancer

Abstract

Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide, and the 5-year survival rate is still low despite advances in diagnosis and therapeutics. A long noncoding RNA (lncRNA) HOX antisense intergenic RNA (HOTAIR) has been revealed to play important roles in NSCLC carcinogenesis but the detailed mechanisms are still unclear. In the current study, we aimed to investigate the regulation between the lncRNA HOTAIR and p53 in the NSCLC patient samples and cell lines. Our results showed that HOTAIR expression was significantly higher in the cancer tissues than that in the adjacent normal tissue, and was negatively correlated with p53 functionality rather than expression. When p53 was overexpressed in A549 cells, the lncRNA HOTAIR expression was downregulated, and the cell proliferation rate and cell invasion capacity decreased as a consequence. We identified two binding sites of p53 on the promoter region of HOTAIR, where the p53 protein would bind to and suppress the HOTAIR mRNA transcription. Inversely, overexpression of lncRNA HOTAIR inhibited the expression of p53 in A549 cells. Mechanistic studies revealed that HOTAIR modified the promoter of p53 and enhanced histone H3 lysine 27 trimethylation (H3K27me3). These studies identified a specific negative regulation loop of lncRNA HOTAIR and p53 in NSCLC cells, which revealed a new understanding of tumorigenesis in p53 dysfunction NSCLC cells.

Identification and Analysis of P53-Mediated Competing Endogenous RNA Network in Human Hepatocellular Carcinoma

“…We also observed the expression level of H19 was 2.21 folds lower in treatment group than control group, which is a lncRNA that has a functional link with p53 38 . In addition, HOTAIR (Fold Change = 8.3259) could form a negative regulation loop with p53 in NSCLC cells 39 . Moreover, previously confirmed miRNA targets of p53 have also been found such as hsa-miR-34b-5p (Fold Change = 145.6538), hsa-miR-34c-5p (Fold Change = 11.5899) 40 , hsa-miR-200a-3p (Fold Change = 77.6115) and hsa-miR-200b-5p (Fold Change = 24.4659) 12 .…”

Expression of the long non-coding RNA HOTAIR as a prognostic factor in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis

“…HOTAIR is also able to cooperate with the LSD1 complex and can be regulated by different factors such as miR141, Ago2, c-Myc, TGF-β and small interfering RNAs (siRNAs) [ 12 ]. It is also involved in a regulatory control of p53 expression [ 13 ]. Different studies suggest that HOTAIR plays an important role in the metastatic process and may be a predictor of poor patient prognosis when highly expressed [ 14 – 17 ].…”

The role of long noncoding RNA-LET in cell proliferation and invasion of nasopharyngeal carcinoma and its mechanism

“…The ERK1/2 pathway, activated by MEK1/2,32 plays key roles in the regulation of multiple biological activities, including cell proliferation, differentiation, cell cycle transition and survival, and constitutive activation of the ERK1/2 pathway contributes to tumorigenesis, or cancer growth, and increases the cell death threshold 33. The ERK1/2 pathway can regulate the expression of CXCR4 and cyclin D1, which is responsible for the G1/S transition 34. Recent research has demonstrated that in the human NPC cell line CNE1, cell growth and cell cycle were suppressed mainly by inhibiting the phosphorylation and kinase activity of ERK1/2 35.…”