Oncotarget

Research Papers:

The 5′-untranslated region of p16INK4a melanoma tumor suppressor acts as a cellular IRES, controlling mRNA translation under hypoxia through YBX1 binding

Alessandra Bisio _, Elisa Latorre, Virginia Andreotti, Brigitte Bressac-de Paillerets, Mark Harland, Giovanna Bianchi Scarra, Paola Ghiorzo, Robert C. Spitale, Alessandro Provenzani, Alberto Inga

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Oncotarget. 2015; 6:39980-39994. https://doi.org/10.18632/oncotarget.5387

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Abstract

Alessandra Bisio1, Elisa Latorre2, Virginia Andreotti3, Brigitte Bressac-de Paillerets4, Mark Harland5, Giovanna Bianchi Scarra3, Paola Ghiorzo3, Robert C. Spitale6, Alessandro Provenzani2, Alberto Inga1

1Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy

2Laboratory of Genomic Screening, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy

3Laboratory of Genetics of Rare Hereditary Cancers, DiMI, University of Genoa, Italy and IRCCS AOU San Martino-IST, Genoa, Italy

4Service de Génétique, Institut Gustave Roussy, Villejuif, France

5Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK

6Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA

Corresponding to:

Alberto Inga e-mail: inga@science.unitn.it

Alessandra Bisio e-mail: bisio@science.unitn.it

Keywords: p16INK4a, YBX1, melanoma, IRES, hypoxia

Received: July 14, 2015     Accepted: October 05, 2015     Published: October 17, 2015

ABSTRACT

CDKN2A/p16INK4a is an essential tumor suppressor gene that controls cell cycle progression and replicative senescence. It is also the main melanoma susceptibility gene. Here we report that p16INK4a 5′UTR mRNA acts as a cellular Internal Ribosome Entry Site (IRES). The potential for p16INK4a 5′UTR to drive cap-independent translation was evaluated by dual-luciferase assays using bicistronic and monocistronic vectors. Results of reporters’ relative activities coupled to control analyses for actual bicistronic mRNA transcription, indicated that the wild type p16INK4a 5′UTR could stimulate cap-independent translation. Notably, hypoxic stress and the treatment with mTOR inhibitors enhanced the translation-stimulating property of p16INK4a 5′UTR. RNA immunoprecipitation performed in melanoma-derived SK-Mel-28 and in a patient-derived lymphoblastoid cell line indicated that YBX1 can bind the wild type p16INK4a mRNA increasing its translation efficiency, particularly during hypoxic stress. Modulation of YBX1 expression further supported its involvement in cap-independent translation of the wild type p16INK4a but not a c.-42T>A variant. RNA SHAPE assays revealed local flexibility changes for the c.-42T>A variant at the predicted YBX1 binding site region. Our results indicate that p16INK4a 5′UTR contains a cellular IRES that can enhance mRNA translation efficiency, in part through YBX1.

Author Information

Alessandra Bisio
Primary Contact  _

Elisa Latorre

Virginia Andreotti

Brigitte Bressac-de Paillerets

Mark Harland

Giovanna Bianchi Scarra

Paola Ghiorzo

Robert C. Spitale

Alessandro Provenzani

Alberto Inga


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PII: 5387