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

• Published in: The Journal of clinical investigation Vol. 128; no. 4; pp. 1442 - 1457
• Main Authors: Xie, Yuanyuan, Cao, Zhen, Wong, Elissa Wp, Guan, Youxin, Ma, Wenfu, Zhang, Jenny Q, Walczak, Edward G, Murphy, Devan, Ran, Leili, Sirota, Inna, Wang, Shangqian, Shukla, Shipra, Gao, Dong, Knott, Simon Rv, Chang, Kenneth, Leu, Justin, Wongvipat, John, Antonescu, Cristina R, Hannon, Gregory, Chi, Ping, Chen, Yu
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2018
• Subjects: Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Animals; Biomedical research; Cancer; Carcinogenesis; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cellular signal transduction; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; ETS protein; Extracellular signal-regulated kinase; Extracellular signal-regulated kinases; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gastrointestinal cancer; Gene expression; Genetic aspects; Genomes; Genomics; Health aspects; Humans; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, SCID; Mutation; Phosphorylation; Prostate; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ets - genetics; Proto-Oncogene Proteins c-ets - metabolism; RNA-mediated interference; Signal transduction; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome - drug effects; Transcriptome - genetics; Tumorigenesis; Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Vemurafenib - pharmacology; Xenograft Model Antitumor Assays; Signal transduction; Oncology; Melanoma; Therapeutics; Cancer
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI94840

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.