2009年8月21日，顶级学术期刊CELL发表北京大学医学部生物化学与分子生物学系尚永丰教授实验室的研究论文。论文题目为“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）。王艳博士为第一作者，尚永丰教授为责任作者。
乳腺癌是女性最常见的恶性肿瘤之一，而乳腺癌转移是导致患者死亡的主要原因。乳腺癌转移的分子机理目前还不完全清楚。LSD1是第一个被发现的组蛋白去甲基化酶，理论上对基因转录起广泛调控作用，但近期研究却表明LSD1只参与一些特异的细胞信号通路的调控而且与多种肿瘤的发生发展高度相关，提示这一看似简单的酶在生理病理上有着复杂的作用机制。尚永丰教授研究小组利用生物化学、分子生物学、细胞生物学、遗传学、基因组学、临床标本实验和动物实验等综合技术手段，发现：LSD1是Mi-2/NuRD复合体的一个内在亚基；LSD1/NuRD复合体在乳腺癌细胞调控一系列在上皮-间质细胞转换（epithelial-to-mesenchymal transition）中起关键作用的基因，包括TGFb1；乳腺癌病例样本中LSD1表达水平被下调且与TGFb1的表达水平呈负相关。上皮-间质细胞转换是癌症发生转移的关键步骤。尚永丰教授课题组进一步实验证明LSD1能抑制乳腺癌的侵袭和转移，从而揭示了LSD1这一表观调控因子在抑制乳腺癌转移中有着非常重要的作用。
该研究证明NuRD复合体除具有染色质重塑ATP酶和组蛋白去乙酰化酶活性外，还具有组蛋白去甲基化酶的活性，揭示了组蛋白去乙酰化和组蛋白去甲基化这两种重要的组蛋白修饰在染色质重塑中相互协调作用的机理，对认识表观遗传调控的分子机制具有开创性的理论意义。此外，尚永丰教授实验室的研究显示LSD1能够抑制乳腺癌的转移，为乳腺癌转移的干预提供了新的可能的分子靶点。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
