Pellino-1 promotes lung carcinogenesis via the stabilization of Slug and Snail through K63-mediated polyubiquitination

Abstract

Pellino-1 is an E3 ubiquitin ligase acting as a critical mediator for a variety of immune receptor signaling pathways, including Toll-like receptors, interleukin-1 receptor and T-cell receptors. We recently showed that the Pellino-1-transgenic (Tg) mice developed multiple tumors with different subtypes in hematolymphoid and solid organs. However, the molecular mechanism underlying the oncogenic role of Pellino-1 in solid tumors remains unknown. Pellino-1-Tg mice developed adenocarcinoma in the lungs, and Pellino-1 expression was higher in human lung adenocarcinoma cell lines compared with non-neoplastic bronchial epithelial cell lines. Pellino-1 overexpression increased the cell proliferation, survival, colony formation, invasion and migration of lung adenocarcinoma cells, whereas Pellino-1 knock-down showed the opposite effect. Pellino-1 overexpression activated PI3K/Akt and ERK signaling pathways and elicited an epithelial–mesenchymal transition (EMT) phenotype of lung adenocarcinoma cells. Pellino-1-mediated EMT was demonstrated through morphology, the upregulation of Vimentin, Slug and Snail expression and the downregulation of E-cadherin and β-catenin expression. Notably, Pellino-1 had a direct effect on the overexpression of Snail and Slug through Lys63-mediated polyubiquitination and the subsequent stabilization of these proteins. Pellino-1 expression level was significantly correlated with Snail and Slug expression in human lung adenocarcinoma tissues, and lung tumors from Pellino-1-Tg mice showed Snail and Slug overexpression. The Pellino-1-mediated increase in the migration of lung adenocarcinoma cells was mediated by Snail and Slug expression. Taken together, these results show that Pellino-1 contributes to lung tumorigenesis by inducing overexpression of Snail and Slug and promoting EMT. Pellino-1 might be a potential therapeutic target for lung cancer.

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

“…6f). Peli1 is also reported to activate Akt [38,39], which is an important signaling in the regulation of neuropathic pain [40,41]. We found that knocking down Peli1 induced a significant reduction in Akt phosphorylation by 65.1% in the ipsilateral spinal cord, in comparison with scrambled shRNA control (Fig.…”

TGFβ-Activated USP27X Deubiquitinase Regulates Cell Migration and Chemoresistance via Stabilization of Snail1

“…1A). Probably, these DUBs might remove other ubiquitination events that have been associated with Snail1 stability, such as Snail1 K63 polyubiquitination mediated by Pellino E3 ligase (36) or A20-dependent Snail1 multimonoubiquitination (37).…”

Identification of MTHFD2 as a novel prognosis biomarker in esophageal carcinoma patients based on transcriptomic data and methylation profiling

“…Overexpression of PELI1 increases cell proliferation and survival, and contributes to lung tumorigenesis by promoting the epithelial to mesenchymal transition. [ 49 ] Furthermore, PELI1 promotes cell survival and chemoresistance by upregulating the expression of cIAP2 in lung cancer. [ 50 ] Taken together, these findings suggest that PELI1 might be a potential therapeutic target in some tumor types.…”