title: In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma.
abstract: We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAF(V600E) to promote melanomagenesis.
authors: Cancer Genetics Program, Division of Genetics, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Harvard Medical School, Boston, MA 02215, USA.
authors: Florian A
authors: FA
authors: Karreth
authors: Yvonne
authors: Y
authors: Tay
authors: Daniele
authors: D
authors: Perna
authors: Ugo
authors: U
authors: Ala
authors: Shen Mynn
authors: SM
authors: Tan
authors: Alistair G
authors: AG
authors: Rust
authors: Gina
authors: G
authors: DeNicola
authors: Kaitlyn A
authors: KA
authors: Webster
authors: Dror
authors: D
authors: Weiss
authors: Pedro A
authors: PA
authors: Perez-Mancera
authors: Michael
authors: M
authors: Krauthammer
authors: Ruth
authors: R
authors: Halaban
authors: Paolo
authors: P
authors: Provero
authors: David J
authors: DJ
authors: Adams
authors: David A
authors: DA
authors: Tuveson
authors: Pier Paolo
authors: PP
authors: Pandolfi
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D016254:Mutagenesis, Insertional; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D020413:3' Untranslated Regions; D018398:Homeodomain Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse