title: Selective requirement for Mediator MED23 in Ras-active lung cancer.
abstract: K-RAS-activating mutations occur frequently in non-small cell lung cancer, leading to aberrant activation of the Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23 deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. The transcription factor ELK1, which is phosphorylated by MAPK for relaying Ras signaling to MED23, also was required for the Ras-driven oncogenesis. Transcriptome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell-cycle and -proliferation functions to support the Ras dependency. Furthermore, MED23 was up-regulated by Ras transformation in correlation with the strength of Ras signaling as indicated by the ELK1 phosphorylation level and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicted better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the "Ras-addiction" of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences-Max Planck Institute Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C494112:ELK1 protein, human; C492159:MED23 protein, human; D056892:Mediator Complex; D050807:ets-Domain Protein Elk-1; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins