EZH2-DNMT1-mediated epigenetic silencing of miR-142-3p promotes metastasis through targeting ZEB2 in nasopharyngeal carcinoma

Abstract

Human nasopharyngeal carcinoma (NPC) has the highest metastatic rate in head and neck. However, the mechanisms underlying NPC metastasis remain unclear. Here using propensity-score-matched miRNA microarray analysis, miR-142-3p is identified to be the most correlated with distant-metastasis-free survival and downregulated in paraffin-embedded NPC with distant metastasis, which is validated in both internal cohort and external GEO dataset from Canada. miR-142 locus hypermethylation was observed and found to be associated with miR-142-3p downregulation in metastatic NPC. Furthermore, miR-142-3p was epigenetically silenced by EZH2-recruited DNMT1 and suppressed NPC cell metastasis and EMT. Intersecting PCR array gene profiling with bioinformatic prediction, we identify ZEB2 as a direct and functional target of miR-142-3p in NPC. Reversal of miR-142-3p silencing efficiently suppresses NPC cell invasion and metastasis. Moreover, epigenetic miR-142 hypermethylation is correlated with unfavorable prognosis in both training and validation cohorts. This study identifies miR-142-3p as a key suppressive regulator in NPC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-142-3p silencing, providing a potential prognostic marker and therapeutic target to combat NPC metastasis.

Construction and Analysis of lncRNA-mediated ceRNA Network in Nasopharyngeal Carcinoma Based on Weighted Correlation Network Analysis

“…Among the 15 miRNAs in the ceRNAs, hsa-miR-142-3p was demonstrated to be down-regulated in NPC, and a high level of hsa-miR-142-3p indicated favorable prognosis, which was consistent with the previous studies [39,40]. Li Y et al revealed that miR-142-3p was epigenetically silenced by EZH2-recruited DNMT1 and suppress NPC cell metastasis and EMT through targeting ZEB2 [41]. However, Qi et al reported that miR-142-3p inhibits the expression of SOCS6 and promotes cell proliferation in NPC [42].…”

Construction and Analysis of lncRNA-mediated ceRNA Network in Nasopharyngeal Carcinoma Based on Weighted Correlation Network Analysis

“…Among the 15 miRNAs in the ceRNAs, hsa-miR-142-3p was demonstrated to be down-regulated in NPC, and a high level of hsa-miR-142-3p indicated favorable prognosis, which was consistent with the previous studies [16,42]. Li Y et al revealed that miR-142-3p was epigenetically silenced by EZH2-recruited DNMT1 and suppress NPC cell metastasis and EMT through targeting ZEB2 [43]. However, Qi et al…”

<p>miR-100 Inhibits Cell Growth and Proliferation by Targeting HOXA1 in Nasopharyngeal Carcinoma</p>

“…10,12 The dysregulated miRNAs play an important role in NPC tumorigenesis and progression by promoting NPC cell proliferation, invasion, and angiogenesis. [13][14][15][16] It has been found that miR-125b is upregulated in NPC, and it can promote NPC cell proliferation and inhibit cell apoptosis by targeting A20 and activating the NF-kB signaling pathway. 13 miR-506 can inhibit NPC tumor growth and metastasis through inactivating the Wnt/β-catenin signaling pathway by targeting LHX2.…”

“…14 EZH2-DNMT1mediated epigenetic silencing of miR-142-3p promotes NPC cell invasion and metastasis by targeting ZEB2. 15 miR-23a can promote NPC cell growth, migration, and angiogenesis by targeting TSGA10. 16 Here, in our present study, we found that miR-100 was obviously decreased in NPC tissue samples by analyzing three publicly available microarray data.…”

“…[7][8][9] It has been also found that miRNA expression is dysregulated in NPC, [10][11][12] and the dysregulated miRNAs can promote NPC cell proliferation, invasion, and angiogenesis, including miR-125b, miR-506, miR-142-3p, miR-23a, and so on. [13][14][15][16] Thus, previous studies indicate that miRNA plays vital roles in NPC carcinogenesis and development. It also should be noted that further exploration of the function and mechanism of miRNA involved in NPC development and progression would provide novel therapeutic targets.…”