Abstract

mTOR signaling pathway is deregulated in most cancers and uncontrolled cell cycle progression is a hallmark of cancer cell. However, the precise molecular mechanisms of the regulation of DNA replication and chromatin metabolism by mTOR signaling are largely unknown. We herein report that mTOR signaling promotes the loading of MCM2-7 helicase onto chromatin and upregulates DNA replication licensing factor CDC6. Pharmacological inhibition of mTOR kinase resulted in CHK1 checkpoint activation and decreased MCM2-7 replication helicase and PCNA associated with chromatins. Further pharmacological and genetic studies demonstrated CDC6 is positively controlled by mTORC1-S6K1 and mTORC2 signaling. miRNA screening revealed mTOR signaling suppresses miR-3178 thereby upregulating CDC6. Analysis of TCGA data found that CDC6 is overexpressed in most cancers and associates with the poor survival of cancer patients. Our findings suggest that mTOR signaling may control DNA replication origin licensing and replisome stability thereby cell cycle progression through CDC6 regulation.

Details

Title
mTOR Signaling Upregulates CDC6 via Suppressing miR-3178 and Promotes the Loading of DNA Replication Helicase
Author
Wu, Xianjin 1 ; Li, Shenghua 1 ; Hu, Xing 1 ; Xiang, Xiaoliang 1 ; Halloran, Megan 2 ; Yang, Linlin 2 ; Williams, Terence M 2 ; Houghton, Peter J 3 ; Shen, Changxian 2   VIAFID ORCID Logo  ; He, Zhengfu 4 

1  Key Laboratory of Hunan Province for Study and Utilization of Ethnic Medicinal Plant Resources, College of Biological and Food Engineering, Huaihua University, Huaihua, China 
2  Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA 
3  The Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 
4  Department of Thoracic Surgery, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China 
Pages
1-8
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-46052-8
ProQuest document ID
2253821259
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.