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COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors
Yuanyuan Xie, … , Ping Chi, Yu Chen
Yuanyuan Xie, … , Ping Chi, Yu Chen
Published January 23, 2018
Citation Information: J Clin Invest. 2018;128(4):1442-1457. https://doi.org/10.1172/JCI94840.
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Research Article Oncology Therapeutics

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

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Abstract

Aberrant activation of MAPK signaling leads to the activation of oncogenic transcriptomes. How MAPK signaling is coupled with the transcriptional response in cancer is not fully understood. In 2 MAPK-activated tumor types, gastrointestinal stromal tumor and melanoma, we found 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 the players involved in this process, we performed a pooled genome-wide RNAi screen using a fluorescence-based ETV1 protein stability sensor and identified COP1, DET1, DDB1, UBE3C, PSMD4, and COP9 signalosome members. COP1 or DET1 loss led to decoupling between MAPK signaling and the 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 the 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.

Authors

Yuanyuan Xie, Zhen Cao, Elissa W.P. Wong, Youxin Guan, Wenfu Ma, Jenny Q. Zhang, Edward G. Walczak, Devan Murphy, Leili Ran, Inna Sirota, Shangqian Wang, Shipra Shukla, Dong Gao, Simon R.V. Knott, Kenneth Chang, Justin Leu, John Wongvipat, Cristina R. Antonescu, Gregory Hannon, Ping Chi, Yu Chen

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Figure 8

COP1 loss mediates resistance to MAPK pathway inhibitors in vivo.

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COP1 loss mediates resistance to MAPK pathway inhibitors in vivo.
(A and...
(A and B) Immunoblots of 2 representative GIST-T1 (A) and A375 (B) xenografted tumors with (sgCOP1) or without COP1 (sgGFP) knockout, explanted 2 days after drug treatment with the agents by oral gavage, as indicated. Vehicle: water; imatinib: 80 mg/kg twice daily; vemurafenib: 100 mg/kg twice daily. sgGFP, control guide; sgCOP1, single guide targeting COP1. (C and D) Growth curves of GIST-T1 (C) and A375 (D) xenografts in SCID mice over time with treatment by oral gavage. Vehicle: water; imatinib: 80 mg/kg twice daily; vemurafenib: 75 mg/kg twice daily for days 1–7 and increased to 100 mg/kg for days 8–14. GIST-T1 xenografts: sgGFP vehicle (n = 8); sgGFP imatinib (n = 18); sgCOP1 vehicle (n = 8); and sgCOP1 imatinib (n = 18). A375 xenografts: sgGFP vehicle (n = 10); sgGFP vemurafenib (n = 12); sgCOP1 vehicle (n = 8); and sgCOP1 vemurafenib (n = 12). Error bar indicate the mean ± SEM. **P = 0.0043, ***P = 0.0002, and ****P < 0.0001, by 2-tailed, unpaired t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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