Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells

Molecular Oncology. 2020;14(2):347-362 DOI 10.1002/1878-0261.12609

 

Journal Homepage

Journal Title: Molecular Oncology

ISSN: 1574-7891 (Print); 1878-0261 (Online)

Publisher: Wiley

Society/Institution: Federation of European Biochemical Societies

LCC Subject Category: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens

Country of publisher: Netherlands

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Pablo Pérez‐Moreno (Departamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago Chile)

Sebastián Indo (Departamento de Tecnología Médica Facultad de Medicina Universidad de Chile Santiago Chile)

Ignacio Niechi (Instituto de Bioquímica y Microbiología Facultad de Ciencias Universidad Austral de Chile Valdivia Chile)

Hernán Huerta (Departamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago Chile)

Pablo Cabello (Departamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago Chile)

Lilian Jara (Programa de Genética Humana Instituto de Ciencias Biomédicas Facultad de Medicina Universidad de Chile Santiago Chile)

Francisco Aguayo (Departamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago Chile)

Manuel Varas‐Godoy (Centro de Investigación Biomédica Facultad de Medicina Universidad de Los Andes Santiago Chile)

Verónica A. Burzio (Facultad de Ciencias de la Vida Universidad Andrés Bello Santiago Chile)

Julio C. Tapia (Departamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago Chile)

EDITORIAL INFORMATION

Peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 10 weeks

 

Abstract | Full Text

Endothelin‐1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin‐1 rely on its activation by endothelin‐converting enzyme‐1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness. The N terminus of ECE1c is phosphorylated by protein kinase CK2 (also known as casein kinase 2), and this enhances its stability and promotes invasiveness in colorectal cancer cells. However, it is not known how phosphorylation improves stability and why this is correlated with increased aggressiveness. We hypothesized that CK2 phosphorylation protects ECE1c from N‐terminal ubiquitination and, consequently, from proteasomal degradation. Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1cK6R) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib. Furthermore, colorectal cancer cells overexpressing ECE1cK6R displayed enhanced cancer stem cell (CSC) traits, including increased stemness gene expression, chemoresistance, self‐renewal, and colony formation and spheroid formation in vitro, as well as enhanced tumor growth and metastasis in vivo. These findings suggest that CK2‐dependent phosphorylation enhances ECE1c stability, promoting an increase in CSC‐like traits. Therefore, phospho‐ECE1c may be a biomarker of poor prognosis and a potential therapeutic target for colorectal cancer.