The Evi5 oncogene promotes laryngeal cancer cells proliferation by stabilizing c-Myc protein

Abstract

Background: The Ecotropic viral integration site 5 (Evi5) is recognized as a potential oncogene and a cell cycle regulator. Evi5 regulates the abundance of Emi1, an inhibitor of the anaphase-promoting complex/cyclosome, to govern mitotic fidelity. Evi5 has been shown to be dysregulated in several cancer types. However, the expression and biological function of Evi5 in human laryngeal squamous cell carcinoma (LSCC) are still unknown.Methods: Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing was used to generate Evi5 knockout (KO) LSCC cells. The proliferation and cell cycle distribution of LSCC cells was determined. The effect of Evi5 on LSCC tumor growth in vivo was studied in a tumor xenograft model in mice. The interaction between Evi5 and c-Myc was detected by immunoprecipitation (IP) assay. Luciferase assay was used to determine the transcriptional activity of c-Myc.Results: Here, we show that Evi5 controls LSCC tumorigenesis via the stabilization of c-MYC oncogene. CRISPR-mediated knockout (KO) of Evi5 decreased the proliferation and decreased colony formation ability of LSCC cells. Knockout of Evi5 caused increased G1 phase and decreased S phase cells. In the tumor-bearing nude mice, The transplanted tumors originated from Evi5-KO TU212 cells were significantly decreased when compared with control TU212 cells. At the molecular level, we found that Evi5 interacted with c-MYC and Evi5 antagonized E3 ligase FBXW7-mediated ubiquitination and degradation of c-Myc protein, and promoted c-Myc-dependent transactivation. Conclusion:Given the critical role of c-Myc in tumorigenesis, our data suggest that Evi5 is a potential therapeutic target in LSCC, and inhibition of Evi5 should be a prospective strategy for LSCC therapy.

The role of ubiquitination and deubiquitination in cancer metabolism

“…FBXL16 can competitively bind with c-Myc without inducing ubiquitination of c-Myc, thereby rescuing c-Myc from FBXW7-mediated degradation [164]. Interaction with Evi5 also antagonizes FBXW7-mediated ubiquitination of c-Myc protein in laryngeal squamous cell carcinoma [165]. Phosphorylated ANXA2 interacts with MYC and inhibits ubiquitindependent proteasomal degradation of MYC protein in esophageal cancer [166].…”

FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

“…In adult T-cell leukemia/lymphoma (ATLL) cell lines, the mRNA and protein level of c-MYC is higher than normal due to the aberrations of FBXW7 expression, which is correlated with ATLL proliferation and poor prognosis of patients ( 32 ). Another study has disclosed that the oncogene Ecotropic viral integration site 5 (Evi5) accelerates laryngeal cancer cell proliferation by counteracting FBXW7, thus facilitating the accumulation of its substrate c-MYC ( 33 ).…”

Identification of diagnostic biomarkers for idiopathic pulmonary hypertension with metabolic syndrome by bioinformatics and machine learning

“…EVI5 has different regulatory roles in cell cycle progression, cytokinesis, and cell membrane trafficking. In tumors, EVI5 expression is dysregulated in multiple cancer types, such as non-small-cell lung cancer, laryngeal cancer, and hepatocellular carcinoma, and EVI5 is therefore considered potential oncogenes and cell-cycle regulators [25][26][27] . EVI5 is also a risk factor for multiple sclerosis 28 .…”