Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer

Rengyun Liu, Tao Zhang, Guangwu Zhu and Mingzhao Xing ()
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Rengyun Liu: John Hopkins University School of Medicine
Tao Zhang: John Hopkins University School of Medicine
Guangwu Zhu: John Hopkins University School of Medicine
Mingzhao Xing: John Hopkins University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations are widely found to be a robust genetic background promoting human cancer aggressiveness, but the mechanism is unclear. Here, we demonstrate that the BRAF V600E/MAP kinase pathway phosphorylates and activates FOS, which in turn acts as a transcription factor to bind and activate the GABPB promoter, increasing GABPB expression and driving formation of GABPA-GABPB complex; the latter selectively binds and activates mutant TERT promoter, upregulating TERT expression. Elevated TERT functions as a strong oncoprotein, robustly promoting aggressive behaviors of cancer cells and tumor development. We thus identify a molecular mechanism for the activation of mutant TERT by the BRAF V600E/MAP kinase pathway, in which FOS as a transcriptional factor of GABPB promoter plays a key role in functionally bridging the two oncogenes in cooperatively promoting oncogenesis, providing important cancer biological and clinical implications.

Date: 2018
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DOI: 10.1038/s41467-018-03033-1

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