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Oncogene:新药物治疗尤文氏肉瘤

来源:生物谷 2012-11-27 14:32

2012年11月26日 讯 /生物谷BIOON/ --近日,Huntsman癌症研究所研究人员在一项新的研究中发现一种新的药物可以用来治疗尤文氏肉瘤。该报告刊登在11月26日的Oncogene杂志上。

尤因肉瘤几乎总是由一种致癌蛋白EWS/FLI促发。在实验室中,Lessnick和他的同事发现,一种酶,称为赖氨酸特异性脱甲基酶(LSD-1),与EWS/FLI互动关闭尤文氏肉瘤表达的基因。通过关闭特定的基因,抑制EWS/FLI-LSD1促进尤因肉瘤发展的功效。这使得LSD-1成为一个重要的新药物靶标来治疗尤文氏肉瘤。
 
我们已经知道,EWS/FLI通过与DNA结合的方式发挥作用,如果我们能抑制EWS/FLI,我们就能抑制这种癌症,因为EWS/FLI是尤文氏肉瘤的主调节器。

Lessnick和他的同事们主要在科学实验室完成其基本工作,将LSD-1作为一个可能的新的癌症治疗靶点已经开展了好几年。

研究已经发现LSD-1在几种不同的癌症包括急性白血病,乳腺癌和前列腺癌都具有非常重要的作用。LSD-1直接调节EWS/FLI的功能,实验证明LSD抑制剂对尤文肉瘤模型有效。
 
目前,Lessnick和Sharma一起工作以进一步测试LSD抑制剂在动物模型中的作用,并积极将药物推向临床试验。(生物谷:Bioon.com)

Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma.

S Sankar, R Bell, B Stephens, R Zhuo, S Sharma, D J Bearss, S L Lessnick

Ewing sarcoma provides an important model for transcription-factor-mediated oncogenic transformation because of its reliance on the ETS-type fusion oncoprotein EWS/FLI. EWS/FLI functions as a transcriptional activator and transcriptional activation is required for its oncogenic activity. Here, we demonstrate that a previously less-well characterized transcriptional repressive function of the EWS/FLI fusion is also required for the transformed phenotype of Ewing sarcoma. Through comparison of EWS/FLI transcriptional profiling and genome-wide localization data, we define the complement of EWS/FLI direct downregulated target genes. We demonstrate that LOX is a previously undescribed EWS/FLI-repressed target that inhibits the transformed phenotype of Ewing sarcoma cells. Mechanistic studies demonstrate that the NuRD co-repressor complex interacts with EWS/FLI, and that its associated histone deacetylase and LSD1 activities contribute to the repressive function. Taken together, these data reveal a previously unknown molecular function for EWS/FLI, demonstrate a more highly coordinated oncogenic transcriptional hierarchy mediated by EWS/FLI than previously suspected, and implicate a new paradigm for therapeutic intervention aimed at controlling NuRD activity in Ewing sarcoma tumors.

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