《Nature》癌理论新观点

　　

生物通报道，洛克菲勒大学表观遗传学实验室，Sloan-Kettering癌症研究中心结构生物学实验室，Scripps研究所癌症生物研究实验室的研究者在最近的一期Nature上发表了Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger文章。，提出了癌症机理新的学说。

 

据介绍，癌症多由染色质错误识别所致。一种错误表达的蛋白与DNA螺旋结构上的蛋白错误的结合会启动错误的基因表达，这将导致细胞不受系统检测而错误地生长。

 

几种不同形式的血癌如急性髓细胞样白血病就是由于染色质错误交换或是染色质异位所致。这样的错误会导致蛋白翻译过程出错，产生同源异构的蛋白产物，这些就是染色质识别错误或是基因表达调节错误的结果。然而，这些错误是如何导致癌症产生的呢，这一直都是个谜。

 

斯坦福大学的癌症生物学家Or Gozami表示，Nature新发布的这篇研究成可以说是解开这个谜的答案。它不仅仅有助解开急性髓性白血病之谜，还有助解开其他癌症之谜。

 

 

洛克菲勒大学等处的研究人员认为，在组蛋白的甲基化修饰过程出现的错误可能就是导致癌症发生的原因。如果出现同源异构的蛋白（错误表达）与甲基化酶结合将导致启动错误的细胞周期，这些都可能导致癌症的发生。

 

研究人员首次报告，PHD finger导致的错误组蛋白修饰过程是促使癌变发生的原因。

（生物通 小茜）

生物通推荐原文检索：Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger

Gang G. Wang1, Jikui Song2, Zhanxin Wang2, Holger L. Dormann1, Fabio Casadio1, Haitao Li2, Jun-Li Luo3, Dinshaw J. Patel2 & C. David Allis1

 

Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA

 

Top of pageHistone H3 lysine 4 methylation (H3K4me) has been proposed as a critical component in regulating gene expression, epigenetic states, and cellular identities1. The biological meaning of H3K4me is interpreted by conserved modules including plant homeodomain (PHD) fingers that recognize varied H3K4me states1, 2. The dysregulation of PHD fingers has been implicated in several human diseases, including cancers and immune or neurological disorders3. Here we report that fusing an H3K4-trimethylation (H3K4me3)-binding PHD finger, such as the carboxy-terminal PHD finger of PHF23 or JARID1A (also known as KDM5A or RBBP2), to a common fusion partner nucleoporin-98 (NUP98) as identified in human leukaemias4, 5, generated potent oncoproteins that arrested haematopoietic differentiation and induced acute myeloid leukaemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukaemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukaemic transformation. NUP98–PHD fusion prevented the differentiation-associated removal of H3K4me3 at many loci encoding lineage-specific transcription factors (Hox(s), Gata3, Meis1, Eya1 and Pbx1), and enforced their active gene transcription in murine haematopoietic stem/progenitor cells. Mechanistically, NUP98–PHD fusions act as 'chromatin boundary factors', dominating over polycomb-mediated gene silencing to 'lock' developmentally critical loci into an active chromatin state (H3K4me3 with induced histone acetylation), a state that defined leukaemia stem cells. Collectively, our studies represent, to our knowledge, the first report that deregulation of the PHD finger, an 'effector' of specific histone modification, perturbs the epigenetic dynamics on developmentally critical loci, catastrophizes cellular fate decision-making, and even causes oncogenesis during mammalian development.