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.
Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):E2813-22. doi: 10.1073/pnas.1204311109. Epub 2012 Sep 17.
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.
K-RAS 激活突变在非小细胞肺癌中经常发生，导致 Ras-MAPK 信号通路的异常激活，从而促进恶性表型的发生。然而，Ras 靶向治疗的发展仍然具有挑战性。在这里，我们表明，MED23 是多亚基 Mediator 复合物的一个组成部分，已知其整合信号和基因活性，对 Ras 活性的肺癌是选择性重要的。通过用或不用 Ras 突变筛选大量的人类肺癌细胞系，我们发现 Med23 RNAi 特异性抑制 Ras 活性过度活跃的肺癌细胞的增殖和致瘤性。成纤维细胞中 Med23 的缺失选择性地抑制了由 Ras 诱导的致癌转化，但不抑制由 c-Myc 诱导的致癌转化。转录因子 ELK1 通过 MAPK 磷酸化将 Ras 信号传递到 MED23，它也是 Ras 驱动的致癌所必需的。转录组分析显示，MED23 和 ELK1 共同调节一组共同的靶基因，这些基因富集在调节细胞周期和增殖功能上，以支持 Ras 依赖性。此外，Ras 转化会上调 MED23，与 ELK1 磷酸化水平所指示的 Ras 信号强度相关，并在 Ras 突变的肺癌细胞系和原发性肿瘤样本中发现过度表达。值得注意的是，较低的 Med23 表达预示着 Ras 活性肺癌患者和异种移植小鼠的生存更好。总之，我们的研究结果表明 MED23 在促进肺癌发生的“Ras 成瘾”中具有关键作用，因此为治疗 Ras 活性肺癌提供了一个脆弱的靶点。
