P53-dependent Long Noncoding RNA TUG1 Affects Cell Proliferation In Human Non-small Cell Lung Cancer Throughepigentically Regulating HOXB7 Expression

Lung cancer is a multi-steps process that involves the proto-oncogenes and tumor suppressor genes, genetic and epigenetic changes. Recently, a novel class of transcripts, long noncoding RNAs(lncRNAs), is being identified at a rapid pace. These RNAs act critical roles in diverse biological processes including tumorigenesis. Here, we reported that TUG1, a 7.1-kb long noncoding RNA, recruiting and binding to PRC2, was 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. Further experiments revealed that TUG1 expression was induced by p53(wild type), ChIP performance confirmed that TUG1 was a direct transcriptional target of p53, and the expression of TUG1 was obviously downregulated in p53 knockout mice. Moreover, TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Interestingly, inhibition of TUG1 could upregulate HOXB7 expression, ChIP experiments demonstrated that the promoter of HOXB7 locus was bound by EZH2, a key component of PRC2, and was H3K27-trimethylated. TUG1 could participate in AKT and MAPK pathways through modulating the expression of HOXB7. In addition, overexpression or inhibition of p53 could regulate HOXB7 expression. Furthermore, a reverse correlation between the expression of TUG1 and HOXB7 was noted in NSCLC tissues. These findings suggest that p53-dependent TUG1 epigenetically regulates the expression of HOXB7 through binding to PRC2. TUG1 plays a pivotal role in p53 pathway, the p53/TUG1/PRC2/HOXB7 interaction might serve as important targets for NSCLC diagnosis and therapy.