Lysophosphatidic Acid–Induced EGFR Transactivation Promotes Gastric Cancer Cell DNA Replication by Stabilizing Geminin in the S Phase

Geminin, an inhibitor of the DNA replication licensing factor, chromatin licensing and DNA replication factor (Cdt) 1, is essential for the maintenance of genomic integrity. As a multifunctional protein, geminin is also involved in tumor progression, but the molecular details are largely unknown. He...

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Published inFrontiers in pharmacology Vol. 12; p. 706240
Main Authors Zhao, Haile, Gezi, Gezi, Tian, Xiaoxia, Jia, Peijun, Morigen, Morigen, Fan, Lifei
Format Journal Article
LanguageEnglish
Published Frontiers Media S.A 29.09.2021
Subjects
DNA replication
EGFR
geminin
LPA
Pharmacology
transactivation
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Summary:Geminin, an inhibitor of the DNA replication licensing factor, chromatin licensing and DNA replication factor (Cdt) 1, is essential for the maintenance of genomic integrity. As a multifunctional protein, geminin is also involved in tumor progression, but the molecular details are largely unknown. Here, we found that lysophosphatidic acid (LPA)–induced upregulation of geminin was specific to gastric cancer cells. LPA acted via LPA receptor (LPAR) 3 and matrix metalloproteinases (MMPs) signaling to transactivate epidermal growth factor receptor (EGFR) (Y1173) and thereby stabilize geminin expression level during the S phase. LPA also induced the expression of deubiquitinating protein (DUB) 3, which prevented geminin degradation. These results reveal a novel mechanism underlying gastric cancer progression that involves the regulation of geminin stability by LPA-induced EGFR transactivation and provide potential targets for the signaling pathway and tumor cell–specific inhibitors.
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These authors have contributed equally to this work and share first authorship
Edited by: Yi-Chao Zheng, Zhengzhou University, China
Reviewed by: Orsola di Martino, Washington University in St. Louis, United States
This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
Lukasz Opalinski, University of Wroclaw, Poland
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2021.706240