EZH2 promotes angiogenesis through inhibition of miR-1/Endothelin-1 axis in nasopharyngeal carcinoma

Abstract

Emerging evidence clearly indicates that EZH2 plays a crucial role in tumor angiogenesis. However, the role of EZH2 in angiogenesis is still unknown in nasopharyngeal carcinoma (NPC). We here showed that the elevated EZH2 level was closely associated with an aggressive and poor prognostic phenotype, and was positively correlated with microvessel density (MVD) in NPC tissues. Functional studies showed that EZH2 upregulation promoted cell proliferation, migration and tubule formation of endothelial cells, and knockdown of EZH2 suppressed tumor growth, metastasis and angiogenesis in vivo. Mechanistic investigations revealed that EZH2 inhibited miR-1 transcription via promoter binding activity, leading to enhanced expression of Endothelin-1 (ET-1) which is suppressed by miR-1 targeting of ET-1 3′UTR. Furthermore, knockdown of EZH2 or overexpression of miR-1 exerted anti-angiogenic effect on NPC cells. More importantly, the neutralizing antibody against ET-1 significantly abrogated the pro-angiogenic effect of EZH2, and forced expression of ET-1 rescued the anti-angiogenic effect induced by EZH2 knockdown. In clinical specimens, ET-1 was widely overexpressed and associated with clinical stage and MVD. Taken together, our results identify a novel signaling pathway involved in NPC angiogenesis, and also suggest that EZH2-miR-1-ET-1 axis represents multiple potential therapeutic targets for NPC.

Ezh2, endothelin-1, and cd34 as biomarkers of aggressive cervical squamous cell carcinoma: an immunohistochemical study

“…The present study showed a significant association of ET-1 expression with the advanced stage of CSCC cases and positive lymph node metastasis. Similarly, high ET-1 expression and higher stages of laryngeal carcinoma were found to be associated in other studies (7,19). This could be explained by the fact that the ET-1/ETAR axis can promote EMT, thus enhancing invasion and metastasis.…”

“…It was suggested that EZH2 could affect cancer angiogenesis as it has genes repressor role (7). It helps cancer stem cell self-renewal; cancer stem cells are the seeds of metastatic spread and can differentiate into tumor-associated endothelial cells (17).…”

“…Mechanistic work of that study revealed that EZH2 inhibits miR-1 transcription through promoter binding activity, with the result of increased ET-1 expression which is suppressed by miR-1. Furthermore, EZH2 knockdown or miR-1 overexpression induces anti-angiogenic effect on nasopharyngeal carcinoma cells (7). Further experimental and mechanistic study is needed to prove the angiogenic pathway in CSCC.…”

“…Thus, novel strategies to target both of them are needed (6). Neo-angiogenesis occurs through an interaction between pro-and anti-angiogenic signals induced by endothelial and stromal tumor cells (7).…”

Efficacy of extracts of Celastrus�orbiculatus in suppressing migration and invasion by inhibiting the EZH2/ROCK1 signaling pathway in human nasopharyngeal carcinoma

“…Overexpression of EZH2 was associated with an advanced clinical stage and increased risk of relapse, and EZH2 served as an independent poor prognostic factor for patients with NPC (3,22). Therefore, ROCK1 may be partially involved in EZH2-induced progression of NPC.…”