Post-transcriptional Control of Tumor Cell Autonomous Metastatic Potential by CCR4-NOT Deadenylase CNOT7.

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.
Authors	Farhoud Faraji, Ying Hu, Howard H Yang, Maxwell P Lee, G Sebastian Winkler, Markus Hafner, Kent W Hunter
Journal	PLoS genetics (PLoS Genet) Vol. 12 Issue 1 Pg. e1005820 (Jan 2016) ISSN: 1553-7404 [Electronic] United States
PMID	26807845 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References	CCR4 protein, human CNOT1 protein, human Receptors, CCR4 Repressor Proteins Transcription Factors CNOT7 protein, human Exoribonucleases
Topics	Animals Breast Neoplasms (genetics, pathology) Exoribonucleases Female Gene Expression Regulation Gene Expression Regulation, Neoplastic Humans Mammary Neoplasms, Animal (genetics, pathology) Mice Neoplasm Metastasis RNA Stability (genetics) Receptors, CCR4 (genetics) Repressor Proteins Transcription Factors (genetics) Transcriptome (genetics)

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