RMEL3, a novel BRAFV600E-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma
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Lucas Goedert1,2,*, Cristiano G. Pereira1,*, Jason Roszik3,*, Jessica R. Plaça2,4, Cibele Cardoso1, Guo Chen3, Wanleng Deng3, Vashisht Gopal Yennu-Nanda3, Wilson A. Silva Jr.2,5, Michael A. Davies4, Enilza M. Espreafico1
1Department of Cell and Molecular Biology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
2National Institute of Science and Technology in Stem Cell and Cell Therapy and Center for Cell-Based Therapy, Ribeirão Preto, São Paulo, Brazil
3Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
4Clinical Oncology, Stem Cell and Cell Therapy Program, Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil
5Department of Genetics, Ribeirão Preto Medical School, and Center for Integrative System Biology (CISBi-NAP/USP), University of São Paulo, Ribeirão Preto, São Paulo, Brazil
*These authors have contributed equally to this work
Enilza M. Espreafico, e-mail: [email protected]
Keywords: lncRNA, ncRNA, TCGA, ENSG00000250961, ENST00000506106.1
Received: August 28, 2015 Accepted: April 16, 2016 Published: May 4, 2016
Previous work identified RMEL3 as a lncRNA with enriched expression in melanoma. Analysis of The Cancer Genome Atlas (TCGA) data confirmed RMEL3 enriched expression in melanoma and demonstrated its association with the presence of BRAFV600E. RMEL3 siRNA-mediated silencing markedly reduced (95%) colony formation in different BRAFV600E melanoma cell lines. Multiple genes of the MAPK and PI3K pathways found to be correlated with RMEL3 in TCGA samples were experimentally confirmed. RMEL3 knockdown led to downregulation of activators or effectors of these pathways, including FGF2, FGF3, DUSP6, ITGB3 and GNG2. RMEL3 knockdown induces gain of protein levels of tumor suppressor PTEN and the G1/S cyclin-Cdk inhibitors p21 and p27, as well as a decrease of pAKT (T308), BRAF, pRB (S807, S811) and cyclin B1. Consistently, knockdown resulted in an accumulation of cells in G1 phase and subG0/G1 in an asynchronously growing population. Thus, TCGA data and functional experiments demonstrate that RMEL3 is required for MAPK and PI3K signaling, and its knockdown decrease BRAFV600E melanoma cell survival and proliferation.
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