Abstract
BackgroundLong intergenic noncoding RNA p21 (lincRNA-p21) is considered a target of wild-type p53, but little is known about its regulation by mutant p53 and its functions during the progression of head and neck squamous cell carcinoma (HNSCC).MethodsRNAscope was used to detect the expression and distribution of lincRNA-p21. Chromatin immunoprecipitation and electrophoretic mobility shift assays were performed to analyze the transcriptional regulation of lincRNA-p21 in HNSCC cells. The biological functions of lincRNA-p21 were investigated in vitro and in vivo. RNA immunoprecipitation and pull-down assays were used to detect the direct binding of lincRNA-p21.ResultsLower lincRNA-p21 expression was observed in HNSCC tissues and indicated worse prognosis. Both wild and mutant type p53 transcriptionally regulated lincRNA-p21, but nuclear transcription factor Y subunit alpha (NF-YA) was essential for mutant p53 in the regulation of lincRNA-p21. Ectopic expression of lincRNA-p21 significantly inhibited cell proliferation capacity in vitro and in vivo and vice versa. Moreover, the overexpression of lincRNA-p21 induced G1 arrest and apoptosis. Knockdown NF-YA expression reversed tumor suppressor activation of lincRNA-p21 in mutant p53 cells, not wild-type p53 cells. A negative correlation was observed between lincRNA-p21 and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in HNSCC tissues. High lincRNA-p21 expression inhibited Janus kinase 2 (JAK2)/STAT3 signal activation and vice versa. Further, we observed direct binding to STAT3 by lincRNA-p21 in HNSCC cells, which suppressed STAT3-induced oncogenic potential.ConclusionsOur results revealed the transcriptional regulation of lincRNA-p21 by the mutant p53/NF-YA complex in HNSCC. LincRNA-p21 acted as a tumor suppressor in HNSCC progression, which was attributed to direct binding to STAT3 and blocking of JAK2/STAT3 signaling.
Highlights
Long intergenic noncoding RNA p21 is considered a target of wild-type p53, but little is known about its regulation by mutant p53 and its functions during the progression of head and neck squamous cell carcinoma (HNSCC)
Downregulation of LincRNA-p21 is observed in HNSCC and indicates poor prognosis To investigate the clinical relevance of lincRNA-p21 expression in HNSCC, we first examined 70 HNSCC tissues and 9 normal oral mucosa tissues using an RNAscope assay
From TCGA database, we found that HNSCC patients with low lincRNA-p21 expression had worse prognosis (P = 0.03, Fig. 1g)
Summary
Long intergenic noncoding RNA p21 (lincRNA-p21) is considered a target of wild-type p53, but little is known about its regulation by mutant p53 and its functions during the progression of head and neck squamous cell carcinoma (HNSCC). Despite great progress in genomic and molecular research, the treatment effects on patients with HNSCC remains unsatisfactory [2]. HOTAIR interacts with enhancer of zeste homolog 2 to promote the growth of HNSCC cells [12]. Long intergenic noncoding RNA p21 (lincRNA-p21) was first identified as a repressor of the p53-dependent apoptotic response after DNA damage in mouse embryonic fibroblasts harboring wild-type p53 [16]. P53 transcribes messenger RNAs and noncoding RNAs. Whether lincRNA-p21 participates in carcinogenesis and whether its regulation is dependent on p53 status in HNSCC are still unknown
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