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


Authors: Xie, Y.; Cao, Z.; Wong, E. W. P.; 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. V.; Chang, K.; Leu, J.; Wongvipat, J.; Antonescu, C. R.; Hannon, G.; Chi, P.; Chen, Y.
Article Title: COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors
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. © 2018 American Society for Clinical Investigation. All rights reserved.
Journal Title: Journal of Clinical Investigation
Volume: 128
Issue: 4
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2018-04-02
Start Page: 1442
End Page: 1457
Language: English
DOI: 10.1172/jci94840
PROVIDER: scopus
PMCID: PMC5873878
PUBMED: 29360641
DOI/URL:
Notes: Article -- Export Date: 1 May 2018 -- Source: Scopus
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MSK Authors
  1. Yu Chen
    67 Chen
  2. Cristina R Antonescu
    609 Antonescu
  3. Ping Chi
    45 Chi
  4. Wenfu Ma
    4 Ma
  5. Leili Ran
    17 Ran
  6. Zhen Cao
    15 Cao
  7. Inna Sirota
    6 Sirota
  8. Yuanyuan Xie
    8 Xie
  9. Shipra Shukla
    11 Shukla
  10. Dong Gao
    22 Gao
  11. Wai Pung Elissa Wong
    11 Wong
  12. Devan Anne Murphy
    11 Murphy
  13. Youxin   Guan
    8 Guan
  14. Shangqian   Wang
    13 Wang
  15. Jennifer Qi Zhang
    13 Zhang
  16. Justin Leu
    1 Leu