Elevated DHODH expression promotes cell proliferation via stabilizing ß-catenin in esophageal squamous cell carcinoma.
Cell Death Dis
; 11(10): 862, 2020 10 15.
Article
in En
| MEDLINE
| ID: mdl-33060568
ABSTRACT
As a key enzyme in de novo pyrimidine biosynthesis, the expression level of dihydroorotate dehydrogenase (DHODH) has been reported to be elevated in various types of malignant tumors and its tumor-promoting effect was considered to relate to its pyrimidine synthesis function. Here, we revealed one intriguing potential mechanism that DHODH modulated ß-catenin signaling in esophageal squamous cell carcinoma (ESCC). We demonstrated that DHODH directly bound to the NH2 terminal of ß-catenin, thereby, interrupting the interaction of GSK3ß with ß-catenin and leading to the abrogation of ß-catenin degradation and accumulation of ß-catenin in the nucleus, which in turn, resulted in the activation of ß-catenin downstream genes, including CCND1, E2F3, Nanog, and OCT4. We further demonstrated that the regulation of ß-catenin by DHODH was independent of DHODH catalyzing activity. Univariate and multivariate analyses suggested that DHODH expression might be an independent prognostic factor for ESCC patients. Collectively, our study highlights the pivotal role of DHODH mediated ß-catenin signaling and indicates that DHODH may act as a multi-functional switcher from catalyzing pyrimidine metabolism to regulating tumor-related signaling pathways in ESCC.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Esophageal Neoplasms
/
Oxidoreductases Acting on CH-CH Group Donors
/
Beta Catenin
/
Esophageal Squamous Cell Carcinoma
Type of study:
Prognostic_studies
Limits:
Aged
/
Aged80
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Cell Death Dis
Year:
2020
Document type:
Article