Positive regulation of TAZ expression by EBV-LMP1 contributes to cell proliferation and epithelial-mesenchymal transition in nasopharyngeal carcinoma

Abstract

The Epstein-Barr virus latent membrane protein 1 (LMP1) is an integral membrane protein. LMP1 has been reported to activate the NF-κB and mitogen-activated protein kinase pathways. However, these effects alone are unable to account for the profound oncogenic properties of LMP1. TAZ is one of the nuclear effectors of Hippo-related pathways and highly expressed in many human tumors. Here, we reported that TAZ was frequently expressed in LMP1-positive nasopharyngeal carcinoma. In NPC cell lines, we showed that LMP1 promoted TAZ expression. Gelsolin is an important inhibitor of TAZ activity. Our studies showed that LMP1 interacted with gelsolin, resulting in inhibition of Lats1/2 phosphorylation and improvement of TAZ stability. Furthermore, we revealed that TAZ is important for LMP1-mediated cell proliferation, cancer stem cell-like properties and epithelial-mesenchymal transition. These findings provide new insights into the carcinogenic roles of LMP1 and contribute to further understanding of its oncogenic mechanism.

The Hippo Pathway and Viral Infections

“…In addition, EBV-LMP1 inhibits phosphorylation of LATS1/2 by interacting with gelsolin, thereby stabilizing TAZ and promoting its nuclear translocation. Finally, the knockdown experiment demonstrates that TAZ is critical for LMP1-induced cell proliferation, EMT, and cancer stem cell-like properties in nasopharyngeal carcinoma (He et al, 2017). These findings provide new insights into the carcinogenic effect of the Hippo pathway in EBV-mediated oncogenesis.…”

“…The EBV-encoded latent membrane protein, LMP1, is an essential oncogenic protein in EBV-induced growth transformation of human B lymphocytes (Kulwichit et al, 1998). A recent study reveals that LMP1 promotes the expression of TAZ in nasopharyngeal carcinoma cells (He et al, 2017). LMP1 increases the level of TAZ protein not by inducing its transcription but by increasing protein synthesis and stabilization (He et al, 2017).…”

“…A recent study reveals that LMP1 promotes the expression of TAZ in nasopharyngeal carcinoma cells (He et al, 2017). LMP1 increases the level of TAZ protein not by inducing its transcription but by increasing protein synthesis and stabilization (He et al, 2017). In addition, EBV-LMP1 inhibits phosphorylation of LATS1/2 by interacting with gelsolin, thereby stabilizing TAZ and promoting its nuclear translocation.…”

RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner

“…CSCs of NPC have self-renewal, differentiation, and tumorigenic capabilities and are considered the cause of therapeutic resistance, tumor recurrence, and metastasis 17 – 19 . Variable expression of HIPPO-TAZ regulated by cisplatin treatment 20 or by EBV-LMP1 21 in NPC cells contributes to cancer stem cell-like properties and epithelial-mesenchymal transition. A high frequency of RASSF1A inactivation or down-regulation by gene promoter hypermethylation has been observed in NPC 22 , 23 .…”

CRISPR/Cas9-mediated LMP1 knockout inhibits Epstein-Barr virus infection and nasopharyngeal carcinoma cell growth

“…The oncogenic role of LMP1 has been widely investigated, especially how it can promote epithelial-mesenchymal transition (EMT) and NPC cell proliferation and invasion. It positively regulates TAZ expression [16], stimulates the transcription of eukaryotic translation initiation factor 4E (eIF4E) [17], upregulates high mobility group box 1 (HMGB1), facilitates EBV-LMP1-targeted DNAzyme-induced DNA damage to cause cell cycle arrest [18], and inhibits the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway [19].…”