Downregulation of the long noncoding RNA GAS5-AS1 contributes to tumor metastasis in non-small cell lung cancer.

Ying Wu,Bolin Liu,Xuefei Shi,Hongbing Liu,Hui Lyu,Yong Song

doi:10.1038/srep31093

Abstract

Long noncoding RNA (lncRNA) plays pivotal roles in cancer development. To date, only a small number of lncRNAs have been characterized at functional level. Here, we discovered a novel lncRNA termed GAS5-AS1 as a tumor suppressor in non-small cell lung cancer (NSCLC). The expression of GAS5-AS1 in NSCLC tumors was much lower than that in the adjacent normal lung tissues. The reduced GAS5-AS1 was significantly correlated with larger tumors, higher TNM stages, and lymph node metastasis in NSCLC patients. While ectopic expression or specific knockdown of GAS5-AS1 had no effect on proliferation, cell cycle progression, and apoptosis, it dramatically decreased or increased, respectively, NSCLC cell migration and invasion. Overexpression of GAS5-AS1 in NSCLC cells reduced a cohort of molecules (ZEB1, N-cadherin, Vimentin, and/or Snail1) critical for epithelial-mesenchymal transition (EMT). Furthermore, the DNA demethylating agent 5-aza-2-deoxycytidine failed to upregulate GAS5-AS1 in NSCLC cells, whereas the pan-HDAC inhibitors panobinostat and SAHA significantly induced GAS5-AS1 in a dose-dependent manner. In addition, GAS5-AS1 can be upregulated by specific knockdown of HDAC1 or HDAC3. Collectively, our data suggest that histone modifications play a major role leading to epigenetic silencing of GAS5-AS1 in NSCLC and subsequently promote tumor metastasis via upregulation of several key EMT markers.

Highlights

Which may improve our understanding of the molecular basis of cancer initiation and progression
We examined this lncRNA’s expression in a number of non-small cell lung cancer (NSCLC) cell lines, and discovered a much lower expression of GAS5-AS1 in 4 out of six NSCLC cell lines as compared to human bronchial epithelial (HBE) cells (Fig. 2A)
Tumor metastasis is the major cause of death in patients with NSCLC, understanding the molecular mechanism by which a specific lncRNA is involved in metastasis may provide novel opportunities to identify effective therapy against NSCLC

Summary

Introduction

Which may improve our understanding of the molecular basis of cancer initiation and progression. Histone acetylation in the promoter region can affect lncRNA transcriptional activation[25,26]. It indicated that epigenetic regulatory factors, including histone acetylation or DNA methylation, could manipulate the expression of lncRNAs. Recent studies reveal that lncRNAs play a critical role in NSCLC pathogenesis[27,28], providing a new avenue to explore the biology of this disease. We previously showed that the lncRNA GAS5 (growth arrest-specific transcript 5) was significantly downregulated in NSCLC tissues and cell lines; and elevated expression of GAS5 inhibited cell proliferation and induced apoptosis in NSCLC cells[29]. We have investigated the role of GAS5-AS1 in regulating NSCLC cell migration and invasion and explored the potential mechanism leading to downregulation of GAS5-AS1 in NSCLC

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Results

Conclusion