Abstract
The human ortholog of the Drosophila ecdysoneless gene (ECD) is required for embryonic development and cell-cycle progression; however, its role in cancer progression and metastasis remains unclear. Here, we found that ECD is frequently overexpressed in gastric cancer (GC), especially in metastatic GC, and is correlated with poor clinical outcomes in GC patients. Silencing ECD inhibited GC migration and invasion in vitro and metastasis in vivo, while ECD overexpression promoted GC migration and invasion. ECD promoted GC invasion and metastasis by protecting hnRNP F from ubiquitination and degradation. We identified ZFP91 as the E3 ubiquitin ligase that is responsible for hnRNP F ubiquitination at Lys 185 and proteasomal degradation. ECD competitively bound to hnRNP F via the N-terminal STG1 domain (13-383aa), preventing hnRNP F from interacting with ZFP91, thus preventing ZFP91-mediated hnRNP F ubiquitination and proteasomal degradation. Collectively, our findings indicate that ECD promotes cancer invasion and metastasis by preventing E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation, suggesting that ECD may be a marker for poor prognosis and a potential therapeutic target for GC patients.
Highlights
IntroductionAsian countries, including China, and is the second leading cause of cancer-related mortality worldwide, with an overall 5-year survival rate of less than 25%1,2
Gastric cancer (GC) is a prevalent malignancy in EastAsian countries, including China, and is the second leading cause of cancer-related mortality worldwide, with an overall 5-year survival rate of less than 25%1,2
We investigated ECD mRNA expression in gastric mucosal tissues and GC tissues using three microarray gene expression datasets deposited in the Oncomine database
Summary
Asian countries, including China, and is the second leading cause of cancer-related mortality worldwide, with an overall 5-year survival rate of less than 25%1,2. Most GCs are diagnosed clinically at an advanced disease stage and present with distant metastases, which are the most important cause of cancer-associated death in GC patients. The ecdysoneless (ECD) gene was originally named by authors studying Drosophila melanogaster ECD mutants who exhibited defective development due to reduced production of the steroid hormone, ecdysone, required for insect molting[3]. Subsequent studies showed that the ECD protein is required for cell-autonomous processes in Drosophila development and oogenesis[4].
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