EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promote s NSCLC cell proliferation and metastasis by affecting the epithelial–mesenchymal transition

Abstract

Recent evidence indicates that long noncoding RNAs (lncRNAs) have a critical role in the regulation of cellular processes such as differentiation, proliferation, and metastasis. These lncRNAs are dysregulated in a variety of cancers and many function as tumor suppressors; however, the regulatory factors involved in silencing lncRNA transcription are poorly understood. In this study, we showed that epigenetic silencing of lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) occurs in non-small-cell lung cancer (NSCLC) cells through direct transcriptional repression mediated by the Polycomb group protein enhancer of zeste homolog 2 (EZH2). SPRY4-IT1 is derived from an intron within SPRY4, and is upregulated in melanoma cells; knockdown of its expression leads to cell growth arrest, invasion inhibition, and elevated rates of apoptosis. Upon depletion of EZH2 by RNA interference, SPRY4-IT1 expression was restored, and transfection of SPRY4-IT1 into NSCLC cells resulted in a significant antitumoral effect, both in culture and in xenografted nude mice. Moreover, overexpression of SPRY4-IT1 was found to have a key role in the epithelial–mesenchymal transition through the regulation of E-cadherin and vimentin expression. In EZH2-knockdown cells, which characteristically showed impaired cell proliferation and metastasis, the induction of SPRY4-IT1 depletion partially rescued the oncogenic phenotype, suggesting that SPRY4-IT1 repression has an important role in EZH2 oncogenesis. Of most relevance, translation of these findings into human NSCLC tissue samples demonstrated that patients with low levels of SPRY4-IT1 expression had a shorter overall survival time, suggesting that SPRY4-IT1 could be a biomarker for poor prognosis of NSCLC.

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

“…For PDCD1LG2 and PKD2, there was no publication suggesting their roles in NSCLC. In contrast, the EZH (enhancer of zeste homolog) family appears to play an important role in NSCLC [22][23][24][25][26]. Thus, we explored if EZH1 is a target of miR-17-5p and there was a good alignment between 3 0 -UTR of EZH1 mRNA and miR-17-5p seed sequence (Figure 4(A)).…”

Epigenetic regulation in human melanoma: past and future

“…85 A recent study in non-small cell lung cancer (NSCLC) has found evidence that SPRY4-IT1 controls epithelial-mesenchymal transition (EMT) through regulation of E-cadherin and vimentin expression leading to cell proliferation and metastasis. 86 …”

Long non-coding RNA HOXA transcript at the distal tip as a biomarker for gastric cancer

“…For instance, a lncRNA named SPRY4 intronic transcript 1 (SPRY4-IT1) was reported to be overexpressed in melanoma, renal cell carcinoma, esophageal squamous cell carcinoma, breast cancer, bladder cancer and glioma, and associated with poor prognosis and promotion of tumor growth (24)(25)(26)(27)(28)(29). Certain studies also demonstrated that SPRY4-IT1 expression was decreased in non-small-cell lung cancer and gastric cancer, and acted with significant antitumor function in these two types of cancer (30,31). Similarly, HOTTIP may exhibit a tissue-specific expression pattern and serve a different function in different types of cancer, as with SPRY4-IT.…”