Regulation of Mutant TERT by BRAF V600E/MAP Kinase Pathway Through FOS/GABP in Human Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Feb 10

PMID 29422527

Citations 106

Authors

Rengyun Liu

Tao Zhang

Guangwu Zhu

Mingzhao Xing

Affiliations

Soon will be listed here.

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.

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References

Safaee Ardekani G, Jafarnejad S, Tan L, Saeedi A, Li G . The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012; 7(10):e47054. PMC: 3467229. DOI: 10.1371/journal.pone.0047054. View

Song Y, Lim J, Choi H, Won J, Moon J, Cho S . Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients. Cancer. 2016; 122(9):1370-9. DOI: 10.1002/cncr.29934. View

Stern J, Theodorescu D, Vogelstein B, Papadopoulos N, Cech T . Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 2015; 29(21):2219-24. PMC: 4647555. DOI: 10.1101/gad.269498.115. View

Okazaki K, Sagata N . The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells. EMBO J. 1995; 14(20):5048-59. PMC: 394608. DOI: 10.1002/j.1460-2075.1995.tb00187.x. View

Joseph E, Pratilas C, Poulikakos P, Tadi M, Wang W, Taylor B . The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. 2010; 107(33):14903-8. PMC: 2930420. DOI: 10.1073/pnas.1008990107. View

Monje P, Marinissen M, Gutkind J . Phosphorylation of the carboxyl-terminal transactivation domain of c-Fos by extracellular signal-regulated kinase mediates the transcriptional activation of AP-1 and cellular transformation induced by platelet-derived growth factor. Mol Cell Biol. 2003; 23(19):7030-43. PMC: 193921. DOI: 10.1128/MCB.23.19.7030-7043.2003. View

Maida Y, Yasukawa M, Furuuchi M, Lassmann T, Possemato R, Okamoto N . An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature. 2009; 461(7261):230-5. PMC: 2755635. DOI: 10.1038/nature08283. View

Liu R, Xing M . TERT promoter mutations in thyroid cancer. Endocr Relat Cancer. 2016; 23(3):R143-55. PMC: 4750651. DOI: 10.1530/ERC-15-0533. View

Dahiya S, Haydon D, Alvarado D, Gurnett C, Gutmann D, Leonard J . BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol. 2013; 125(6):901-10. DOI: 10.1007/s00401-013-1120-y. View

10.

Hrdlickova R, Nehyba J, Bose Jr H . Alternatively spliced telomerase reverse transcriptase variants lacking telomerase activity stimulate cell proliferation. Mol Cell Biol. 2012; 32(21):4283-96. PMC: 3486134. DOI: 10.1128/MCB.00550-12. View

11.

Davies H, Bignell G, Cox C, Stephens P, Edkins S, Clegg S . Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-54. DOI: 10.1038/nature00766. View

12.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

13.

Monje P, Hernandez-Losa J, Lyons R, Castellone M, Gutkind J . Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1. J Biol Chem. 2005; 280(42):35081-4. DOI: 10.1074/jbc.C500353200. View

14.

Koh C, Khattar E, Leow S, Liu C, Muller J, Ang W . Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity. J Clin Invest. 2015; 125(5):2109-22. PMC: 4463203. DOI: 10.1172/JCI79134. View

15.

Bell R, Rube H, Kreig A, Mancini A, Fouse S, Nagarajan R . Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015; 348(6238):1036-9. PMC: 4456397. DOI: 10.1126/science.aab0015. View

16.

Xing M, Alzahrani A, Carson K, Shong Y, Kim T, Viola D . Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 2014; 33(1):42-50. PMC: 4268252. DOI: 10.1200/JCO.2014.56.8253. View

17.

Thomas N, Edmiston S, Alexander A, Groben P, Parrish E, Kricker A . Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma. JAMA Oncol. 2015; 1(3):359-68. PMC: 4486299. DOI: 10.1001/jamaoncol.2015.0493. View

18.

Xing M . BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005; 12(2):245-62. DOI: 10.1677/erc.1.0978. View

19.

Nagore E, Heidenreich B, Rachakonda S, Garcia-Casado Z, Requena C, Soriano V . TERT promoter mutations in melanoma survival. Int J Cancer. 2016; 139(1):75-84. PMC: 8238633. DOI: 10.1002/ijc.30042. View

20.

Low K, Tergaonkar V . Telomerase: central regulator of all of the hallmarks of cancer. Trends Biochem Sci. 2013; 38(9):426-34. DOI: 10.1016/j.tibs.2013.07.001. View