2009年8月21日，頂級學(xué)術(shù)期刊CELL發(fā)表北京大學(xué)醫(yī)學(xué)部生物化學(xué)與分子生物學(xué)系尚永豐教授實驗室的研究論文,。論文題目為“LSD1 is a Subunit of the NuRD Complex and Targets the Metastasis Programs in Breast Cancer”（Wang et al, CELL 138: 660-672, 2009. IF 31.253）,。王艷博士為第一作者,，尚永豐教授為責(zé)任作者。
乳腺癌是女性最常見的惡性腫瘤之一,，而乳腺癌轉(zhuǎn)移是導(dǎo)致患者死亡的主要原因,。乳腺癌轉(zhuǎn)移的分子機理目前還不完全清楚,。LSD1是第一個被發(fā)現(xiàn)的組蛋白去甲基化酶,，理論上對基因轉(zhuǎn)錄起廣泛調(diào)控作用，但近期研究卻表明LSD1只參與一些特異的細胞信號通路的調(diào)控而且與多種腫瘤的發(fā)生發(fā)展高度相關(guān),，提示這一看似簡單的酶在生理病理上有著復(fù)雜的作用機制,。尚永豐教授研究小組利用生物化學(xué)、分子生物學(xué),、細胞生物學(xué),、遺傳學(xué)、基因組學(xué),、臨床標(biāo)本實驗和動物實驗等綜合技術(shù)手段,，發(fā)現(xiàn)：LSD1是Mi-2/NuRD復(fù)合體的一個內(nèi)在亞基；LSD1/NuRD復(fù)合體在乳腺癌細胞調(diào)控一系列在上皮-間質(zhì)細胞轉(zhuǎn)換（epithelial-to-mesenchymal transition）中起關(guān)鍵作用的基因,，包括TGFb1,；乳腺癌病例樣本中LSD1表達水平被下調(diào)且與TGFb1的表達水平呈負(fù)相關(guān),。上皮-間質(zhì)細胞轉(zhuǎn)換是癌癥發(fā)生轉(zhuǎn)移的關(guān)鍵步驟。尚永豐教授課題組進一步實驗證明LSD1能抑制乳腺癌的侵襲和轉(zhuǎn)移,，從而揭示了LSD1這一表觀調(diào)控因子在抑制乳腺癌轉(zhuǎn)移中有著非常重要的作用,。
該研究證明NuRD復(fù)合體除具有染色質(zhì)重塑ATP酶和組蛋白去乙酰化酶活性外,，還具有組蛋白去甲基化酶的活性,，揭示了組蛋白去乙酰化和組蛋白去甲基化這兩種重要的組蛋白修飾在染色質(zhì)重塑中相互協(xié)調(diào)作用的機理,，對認(rèn)識表觀遺傳調(diào)控的分子機制具有開創(chuàng)性的理論意義,。此外，尚永豐教授實驗室的研究顯示LSD1能夠抑制乳腺癌的轉(zhuǎn)移,，為乳腺癌轉(zhuǎn)移的干預(yù)提供了新的可能的分子靶點,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cell, Volume 138, Issue 4, 660-672, 21 August 2009 doi:10.1016/j.cell.2009.05.050
LSD1 Is a Subunit of the NuRD Complex and Targets the Metastasis Programs in Breast Cancer
Yan Wang1, Hua Zhang1, Yupeng Chen1, Yimin Sun1, Fen Yang1, Wenhua Yu1, Jing Liang1, Luyang Sun1, Xiaohan Yang1, Lei Shi1, Ruifang Li1, Yanyan Li1, Yu Zhang1, Qian Li1, Xia Yi1 and Yongfeng Shang1, ,
1 Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
Lysine-specific demethylase 1 (LSD1) exerts pathway-specific activity in animal development and has been linked to several high-risk cancers. Here, we report that LSD1 is an integral component of the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex. Transcriptional target analysis revealed that the LSD1/NuRD complexes regulate several cellular signaling pathways including TGFβ1 signaling pathway that are critically involved in cell proliferation, survival, and epithelial-to-mesenchymal transition. We demonstrated that LSD1 inhibits the invasion of breast cancer cells in vitro and suppresses breast cancer metastatic potential in vivo. We found that LSD1 is downregulated in breast carcinomas and that its level of expression is negatively correlated with that of TGFβ1. Our data provide a molecular basis for the interplay of histone demethylation and deacetylation in chromatin remodeling. By enlisting LSD1, the NuRD complex expands its chromatin remodeling capacity to include ATPase, histone deacetylase, and histone demethylase.
