title: RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non-Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway.
abstract: Inactivation of the tumor suppressor gene RASSF1A by promoter hypermethylation represents a key event underlying the initiation and progression of lung cancer. RASSF1A inactivation is also associated with poor prognosis and may promote metastatic spread. In this study, we investigated how RASSF1A inactivation conferred invasive phenotypes to human bronchial cells. RNAi-mediated silencing of RASSF1A induced epithelial-to-mesenchymal transition (EMT), fomenting a motile and invasive cellular phenotype in vitro and increased metastatic prowess in vivo. Mechanistic investigations revealed that RASSF1A blocked tumor growth by stimulating cofilin/PP2A-mediated dephosphorylation of the guanine nucleotide exchange factor GEF-H1, thereby stimulating its ability to activate the antimetastatic small GTPase RhoB. Furthermore, RASSF1A reduced nuclear accumulation of the Hippo pathway transcriptional cofactor Yes-associated protein (YAP), which was reinforced by RhoB activation. Collectively, our results indicated that RASSF1 acts to restrict EMT and invasion by indirectly controlling YAP nuclear shuttling and activation through a RhoB-regulated cytoskeletal remodeling process, with potential implications to delay the progression of RASSF1-hypermethylated lung tumors.
authors.affiliation: Normandie Universite, UMR1086 INSERM, Caen, France. Normandie Universite, UPRES-EA-2608, Caen, France.
authors.forename: Fatéméh
authors.initials: F
authors.lastname: Dubois
authors.affiliation: Normandie Universite, UMR1086 INSERM, Caen, France. Normandie Universite, UPRES-EA-2608, Caen, France.
authors.forename: Maureen
authors.initials: M
authors.lastname: Keller
authors.affiliation: UMR INSERM 1037-CRCT, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Calvayrac
authors.affiliation: UMR CNRS 8161, IBL, Lille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Soncin
authors.affiliation: UCL Cancer Institute, London, United Kingdom.
authors.forename: Lily
authors.initials: L
authors.lastname: Hoa
authors.affiliation: UCL Cancer Institute, London, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
authors.affiliation: U830 INSERM, Institut Curie, Paris, France.
authors.forename: Maria-Carla
authors.initials: MC
authors.lastname: Parrini
authors.affiliation: UMR INSERM 1037-CRCT, Toulouse, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazières
authors.affiliation: Normandie Universite, UMR1086 INSERM, Caen, France.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Vaisse-Lesteven
authors.affiliation: U830 INSERM, Institut Curie, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
authors.affiliation: Normandie Universite, UPRES-EA-2608, Caen, France. guenaelle.levallet@unicaen.fr gerard.zalcman@aphp.fr.
authors.forename: Guénaëlle
authors.initials: G
authors.lastname: Levallet
authors.affiliation: Normandie Universite, UMR1086 INSERM, Caen, France. Pneumologie et Oncologie thoracique, Hôpital Bichat, France. guenaelle.levallet@unicaen.fr gerard.zalcman@aphp.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000091102:YAP-Signaling Proteins; D020743:rhoB GTP-Binding Protein / Q000235:genetics*
chemical_list: C577356:ARHGEF2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C411762:RASSF1 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D020743:rhoB GTP-Binding Protein