COP1-DET1-ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

Xie, Y., Cao, Z., Wong, E. W., Guan, Y., Ma, W., Zhang, J. Q., Walczak, E. G., Murphy, D., Ran, L., Sirota, I., Wang, S., Shukla, S., Gao, D., Knott, S. R., Chang, K., Leu, J., Wongvipat, J., Antonescu, C. R., Hannon, G., Chi, P., Chen, Y. (April 2018) COP1-DET1-ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors. J Clin Invest, 128 (4). pp. 1442-1457. ISSN 0021-9738

URL: https://www.ncbi.nlm.nih.gov/pubmed/29360641
DOI: 10.1172/jci94840

Abstract

Aberrant activation of MAPK signaling leads to activation of oncogenic transcriptomes. How MAPK signaling is coupled with transcriptional response in cancer is not fully understood. In gastrointestinal stromal tumor and melanoma, both with oncogenic MAPK activation, we find that ETV1 and other Pea3-ETS transcription factors are critical nuclear effectors of MAPK signaling that are regulated through protein stability. Expression of stabilized Pea3-ETS factors can partially rescue the MAPK transcriptome and cell viability after MAPK inhibition. To identify players involved in this process, we performed a pooled genome-wide RNAi screen using a novel fluorescence-based ETV1 protein stability sensor, and identified COP1, DET1, DDB1, UBE3C, PSMD4, and COP9 signalosome members. COP1 and DET1 loss led to decoupling between MAPK signaling and downstream transcriptional response, where MAPK inhibition failed to destabilize Pea3 factors and fully inhibit the MAPK transcriptome, thus resulting in decreased sensitivity to MAPK pathway inhibitors. We identified multiple COP1 and DET1 mutations in human tumors that were defective in degradation of Pea3-ETS factors. Two melanoma patients had de novo DET1 mutations arising after vemurafenib treatment. These observations indicate that MAPK signaling-dependent regulation of Pea3-ETS protein stability is a key signaling node in oncogenesis and therapeutic resistance to MAPK pathway inhibition.

Item Type: Paper
Uncontrolled Keywords: Cancer Melanoma Oncology Signal transduction Therapeutics
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Mitogen-activated protein kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > transcriptomes
CSHL Authors:
Communities: CSHL labs > Hannon lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: 2 April 2018
Date Deposited: 20 Feb 2018 20:10
Last Modified: 12 Jun 2018 16:17
PMCID: PMC5873878
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36089

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