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Cancer Res. 2016 Mar 15;76(6):1627-40. doi: 10.1158/0008-5472.CAN-15-1008. Epub 2016 Jan 12.

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.

Author information

1
Normandie Universite, UMR1086 INSERM, Caen, France. Normandie Universite, UPRES-EA-2608, Caen, France.
2
UMR INSERM 1037-CRCT, Toulouse, France.
3
UMR CNRS 8161, IBL, Lille, France.
4
UCL Cancer Institute, London, United Kingdom.
5
U830 INSERM, Institut Curie, Paris, France.
6
Normandie Universite, UMR1086 INSERM, Caen, France.
7
Normandie Universite, UPRES-EA-2608, Caen, France. guenaelle.levallet@unicaen.fr gerard.zalcman@aphp.fr.
8
Normandie Universite, UMR1086 INSERM, Caen, France. Pneumologie et Oncologie thoracique, Hôpital Bichat, France. guenaelle.levallet@unicaen.fr gerard.zalcman@aphp.fr.

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.

PMID:
26759237
DOI:
10.1158/0008-5472.CAN-15-1008
[Indexed for MEDLINE]
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