RMEL3, a novel BRAF(V600E)-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma

Author(s):Show less -

Goedert, Lucas ^{[1, 2]} ; Pereira, Cristiano G. ^[1] ; Roszik, Jason ^{[3, 4]} ; Placa, Jessica R. ^{[2, 5]} ; Cardoso, Cibele ^[1] ; Chen, Guo ^[4] ; Deng, Wanleng ^[4] ; Yennu-Nanda, Vashisht Gopal ^[4] ; Silva, Jr., Wilson A. ^{[2, 3, 6, 7]} ; Davies, Michael A. ^[5] ; Espreafico, Enilza M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Cell & Mol Biol, Sao Paulo - Brazil

^[2] Natl Inst Sci & Technol Stem Cell & Cell Therapy, Sao Paulo - Brazil

^[3] Ctr Cell Based Therapy, Sao Paulo - Brazil

^[4] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 - USA

^[5] Ribeirao Preto Med Sch, Clin Oncol Stem Cell & Cell Therapy Program, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Ctr Integrat Syst Biol CISBI NAP USP, Sao Paulo - Brazil

• Document type: Journal article
• Source: ONCOTARGET; v. 7, n. 24, p. 36711-36718, JUN 14 2016.
• Web of Science Citations: 12

Abstract

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. (AU)

• FAPESP's process: 12/24056-2 - Functional characterization of melanoma-restricted genes (RMELs) associated with melanoma progression and BRAF V600E mutation
• Grantee: Cristiano Gonçalves Pereira
• Support type: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 10/16097-5 - Functional studies and prognostic value of a new gene associated with melanoma progression and oncogenic BRAF
• Grantee: Cristiano Gonçalves Pereira
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/18189-5 - Studying a possible functional circuitry involving microRNAs, MITF, MYO5A/DLC2, RAB27A and connections with the invasion and metastasis cascade
• Grantee: Enilza Maria Espreafico
• Support type: Regular Research Grants
• FAPESP's process: 14/07726-0 - Genomic and functional characterization of genes with expression restricted to melanoma (RMELs)
• Grantee: Lucas Goedert
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC