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
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 Cancer Center Program > Cancer Genetics CSHL labs > Hannon lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | 2 April 2018 |
| Date Deposited: | 20 Feb 2018 20:10 |
| Last Modified: | 05 Nov 2020 22:10 |
| PMCID: | PMC5873878 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36089 |
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