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.
Highlights
Melanoma arises from the malignant transformation of melanocytes that involves numerous genetic alterations affecting multiple signaling pathways including MAPK (Mitogen Activated Protein Kinase), PI3K (Phosphoinositide 3-kinase), cAMP and cyclin D1/CDK4 [1]
To identify the link between MAPK pathway activation and TERT transcription, we investigated the expression of different transcription factors of the ETS family in melanoma cell lines
We found that ETS1, which has previously been shown to be involved in development and invasion of melanoma, was expressed in melanocytes and in all melanoma cell lines that were investigated (Figure 2A and data not shown)
Summary
Melanoma arises from the malignant transformation of melanocytes that involves numerous genetic alterations affecting multiple signaling pathways including MAPK (Mitogen Activated Protein Kinase), PI3K (Phosphoinositide 3-kinase), cAMP and cyclin D1/CDK4 [1]. The discovery of activating somatic mutations within the core promoter region of the TERT gene has provided an insight into the possible cause of telomerase re-expression in some cancer types. Subsequent studies showed occurrence of somatic TERT promoter mutations in a wide range of cancer types [9] In melanoma, those somatic mutations have been associated with increased TERT expression, increased Breslow thickness, tumor ulceration, and poor disease-free and melanoma-specific survival [10, 11]. In melanoma the TERT promoter mutations occur together with BRAF and NRAS mutations more frequently than per chance, suggesting a link between TERT expression and MAPK pathway activation during immortalization of melanocytes via ETS proteins [10]. The transcription factors that have been shown to bind the sites include ETS1, ETS2, ELF1, ELF2, ETV6, p52 NF-κB and GABPA, no study has so far shown link between TERT expression and MAPK activation [16,17,18]
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