title: 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.affiliation: Metastasis Susceptibility Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.|School of Medicine, Saint Louis University, Saint Louis, Missouri, United States of America.
authors.forename: Farhoud
authors.initials: F
authors.lastname: Faraji
authors.affiliation: Center for Biomedical Informatics and Information Technology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Metastasis Susceptibility Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Yang
authors.affiliation: Metastasis Susceptibility Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Maxwell P
authors.initials: MP
authors.lastname: Lee
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: G Sebastian
authors.initials: GS
authors.lastname: Winkler
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Markus
authors.initials: M
authors.lastname: Hafner
authors.affiliation: Metastasis Susceptibility Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kent W
authors.initials: KW
authors.lastname: Hunter
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005095:Exoribonucleases; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D020871:RNA Stability / Q000235:genetics; D054398:Receptors, CCR4 / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: C515354:CCR4 protein, human; C528690:CNOT1 protein, human; D054398:Receptors, CCR4; D012097:Repressor Proteins; D014157:Transcription Factors; C545829:CNOT7 protein, human; D005095:Exoribonucleases