Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas
Files
(Published version)
Date
2016
Authors
Li, Y.
Cheng, H.S.
Chng, W.J.
Tergaonkar, V.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016; 113(50):14402-14407
Statement of Responsibility
Conference Name
Abstract
Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.
School/Discipline
Dissertation Note
Provenance
Description
Data source: Supporting information, http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1611106113/-/DCSupplemental
Access Status
Rights
Copyright 2016 National Academy of Sciences