Post-transcriptional control of tumor cell autonomous metastatic potential by the CCR4-NOT deadenylase CNOT7

Faraji, Farhoud; Hu, Ying; Yang, Howard H.; Lee, Maxwell P.; Winkler, G. Sebastiaan; Hafner, Markus; Hunter, Kent W.

Abstract

Accumulating evidence supports the role of an aberrant transcriptome as a driver of metastatic potential. Deadenylation is a general regulatory node for post-transcriptional control by microRNAs and other determinants of RNA stability. Previously, we demonstrated that the CCR4-NOT scaffold component Cnot2 is an inherited metastasis susceptibility gene. In this study, using orthotopic metastasis assays and genetically engineered mouse models, we show that one of the enzymatic subunits of the CCR4-NOT complex, Cnot7, is also a metastasis modifying gene. We demonstrate that higher expression of Cnot7 drives tumor cell autonomous metastatic potential, which requires its deadenylase activity. Furthermore, metastasis promotion by CNOT7 is dependent on interaction with CNOT1 and TOB1. CNOT7 ribonucleoprotein-immunoprecipitation (RIP) and integrated transcriptome wide analyses reveal that CNOT7-regulated transcripts are enriched for a tripartite 3’UTR motif bound by RNA-binding proteins known to complex with CNOT7, TOB1, and CNOT1. Collectively, our data support a model of CNOT7, TOB1, CNOT1, and RNA-binding proteins collectively exerting post-transcriptional control on a metastasis suppressive transcriptional program to drive tumor cell metastasis.

Citation

Faraji, F., Hu, Y., Yang, H. H., Lee, M. P., Winkler, G. S., Hafner, M., & Hunter, K. W. (2016). Post-transcriptional control of tumor cell autonomous metastatic potential by the CCR4-NOT deadenylase CNOT7. PLoS Genetics, 12, Article e1005820. https://doi.org/10.1371/journal.pgen.1005820

• Journal Article Type: Article
• Acceptance Date: Dec 31, 2015
• Publication Date: Jan 25, 2016
• Deposit Date: Oct 14, 2016
• Publicly Available Date: Oct 14, 2016
• Journal: PLoS Genetics
• Print ISSN: 1553-7390
• Electronic ISSN: 1553-7404
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Article Number: e1005820
• DOI: https://doi.org/10.1371/journal.pgen.1005820
• Public URL: https://nottingham-repository.worktribe.com/output/771704
• Publisher URL: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005820
• Contract Date: Oct 14, 2016