生物谷：使用藥物有可能會激活一個在癌細胞發(fā)育過程中的相關(guān)基因,，來自密歇根大學(xué)（University of Michigan）綜合癌癥治療中心的研究報告稱。此項發(fā)現(xiàn)將有可能借以開發(fā)出新型的癌癥治療方法，一種有望治療多種癌癥的方法,。
現(xiàn)有的一些較為流行的癌癥治療藥物，如Herceptin和Gleevec,，主要是針對一些基因突變而引起蛋白過量表達的情況,。但是癌癥的發(fā)生，有時是一些控制細胞生長的基因被關(guān)閉引起的,。換言之,，研究者可以通過運用這些關(guān)閉的基因來識別或檢測癌癥。但是,，這方面的研究還是空白,。
U-M研究者發(fā)現(xiàn)在一些癌細胞中，一個名為Brahma或BRM的基因會發(fā)生沉默（不是缺失）,。當(dāng)BRM蛋白接觸到一種抑制物后,，研究者可以讓該基因重新恢復(fù)表達。進一步地研究發(fā)現(xiàn),，該基因大約在15%的腫瘤中被關(guān)閉了,，包括肺癌、食道癌,、卵巢癌,、膀胱癌,、結(jié)腸癌和乳腺癌，等,。
研究者通過使用現(xiàn)有的藥物來激活BRM基因,，但是，可能新開發(fā)的藥物將會更加有效,。即便如此,，研究者們對此項有關(guān)癌癥治療領(lǐng)域的發(fā)現(xiàn)感到興奮不已。
“這是‘定向打靶’的,，我們可以檢測到它的效果,。如果我們能開發(fā)出效率更高的藥物，那么勢必會誕生出一類新藥?，F(xiàn)在,，還沒有藥物是專門針對被關(guān)閉的基因的，這是對當(dāng)前只針對基因過量表達的治療方法的一個拓展,。”此項研究的主持者David Reisman介紹說,，他是U-M醫(yī)學(xué)院的內(nèi)科副教授。
研究文章刊登在在線的Oncogene雜志上,，感興趣的讀者可以查閱英文原文,。（引自生命經(jīng)緯）
原始出處:
Oncogene advance online publication 4 June 2007; doi: 10.1038/sj.onc.1210514
The reversible epigenetic silencing of BRM: implications for clinical targeted therapy
S Glaros1, G M Cirrincione1, C Muchardt2, C G Kleer3, C W Michael3 and D Reisman1
1Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA
2Expression Génétique et Maladies, URA1644 du CNRS, Département de Biologie du Développement, Institut Pasteur, Bât. Fernbach, Rue du Docteur Roux, Paris Cedex, France
3Department of Pathology, University of Michigan, Ann Arbor, MI, USA
Correspondence: Dr D Reisman, Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, MRSB2 B570B, Ann Arbor, MI 48103-0686, USA. E-mail: [email protected]
Received 21 November 2006; Revised 2 April 2007; Accepted 2 April 2007; Published online 4 June 2007.
The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRM-related gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.
Keywords:
Brahma, Brahma-related gene 1, BRG1/BRM-associated factor, tumor suppressor, lung cancer, SWI/SNF complex
