Selective requirement for Mediator MED23 in Ras-active lung cancer

	Selective requirement for Mediator MED23 in Ras-active lung cancer
	Yang, X; Zhao, M; Xia, M; Liu, YT; Yan, J; Ji, HB; Wang, G
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2012
卷号	109 期号:41 页码:E2813-E2822
关键词	oncogene addiction transcription cofactor therapeutic target
通讯作者	Wang, G (reprint author), Chinese Acad Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China.,gwang22@sibs.ac.cn
英文摘要	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.
学科主题	Science & Technology - Other Topics
类目[WOS]	Multidisciplinary Sciences
关键词[WOS]	PROTEIN-KINASE CASCADE ; ONCOGENE ADDICTION ; TRANSCRIPTION FACTORS ; COACTIVATOR COMPLEX ; TUMOR SUPPRESSION ; IN-VITRO ; CELLS ; KRAS ; THERAPY ; BETA
收录类别	SCI
语种	英语
WOS记录号	WOS:000310280300011
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/695]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Yang, X,Zhao, M,Xia, M,et al. Selective requirement for Mediator MED23 in Ras-active lung cancer[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2012,109(41):E2813-E2822.
APA	Yang, X.,Zhao, M.,Xia, M.,Liu, YT.,Yan, J.,...&Wang, G.(2012).Selective requirement for Mediator MED23 in Ras-active lung cancer.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,109(41),E2813-E2822.
MLA	Yang, X,et al."Selective requirement for Mediator MED23 in Ras-active lung cancer".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 109.41(2012):E2813-E2822.