Oncotarget

Research Papers:

TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation

Andrelou F. Vallarelli, P. Sivaramakrishna Rachakonda, Jocelyne André, Barbara Heidenreich, Laurence Riffaud, Armand Bensussan, Rajiv Kumar and Nicolas Dumaz _

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Oncotarget. 2016; 7:53127-53136. https://doi.org/10.18632/oncotarget.10634

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Abstract

Andrelou F. Vallarelli1,2,3, P. Sivaramakrishna Rachakonda4, Jocelyne André1,2, Barbara Heidenreich4, Laurence Riffaud1,2, Armand Bensussan1,2, Rajiv Kumar4, Nicolas Dumaz1,2

1INSERM, U976, Skin Research Centre, Hôpital Saint-Louis, Paris, F-75010, France

2 Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France

3Department of Internal Medicine, School of Medicine Sciences, State University of Campinas (UNICAMP), 13083-970, Campinas, SP, Brazil

4Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany

Correspondence to:

Nicolas Dumaz, email: nicolas.dumaz@inserm.fr

Keywords: melanoma, telomerase, ETS1, MAPK pathway, BRAF

Received: March 18, 2016     Accepted: July 09, 2016     Published: July 16, 2016

ABSTRACT

The mechanism of telomerase re-activation in cancer had remained elusive until the discovery of frequent mutations in the promoter of the TERT gene that encodes the catalytic reverse transcriptase subunit of telomerase. We investigated the regulation of TERT expression in melanoma cell lines and our results show that promoter mutations render TERT expression dependent on MAPK activation due to oncogenic BRAF or NRAS mutations. Mutations in the TERT promoter create binding sites for ETS transcription factors. ETS1, expressed in melanoma cell lines, undergoes activating phosphorylation by ERK at Thr38 residue as a consequence of constitutively activated MAPK pathway. We demonstrate that ETS1 binds on the mutated TERT promoter leading to the re-expression of the gene. The inhibition of ETS1 resulted in reduced TERT expression. We provide evidence that the TERT promoter mutations provide a direct link between TERT expression and MAPK pathway activation due to BRAF or NRAS mutations via the transcription factor ETS1.


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