Oh Young Mi, Kwon Young Eun, Kim Joo Mi, Bae Sung Jun, Lee Bo Keun, Yoo Soon Ji, Chung Chin Ha, Deshaies Raymond J, Seol Jae Hong
School of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul 151-742, Korea.
Nat Cell Biol. 2009 Mar;11(3):295-302. doi: 10.1038/ncb1837. Epub 2009 Feb 1.
Chfr is a ubiquitin ligase that functions in the mitotic checkpoint by delaying entry into metaphase in response to mitotic stress. It has been suggested that Chfr is a tumour suppressor as Chfr is frequently silenced in human cancers. To better understand how Chfr activity relates to cell-cycle progression and tumorigenesis, we sought to identify Chfr-interacting proteins using affinity purification combined with mass spectrometry. Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Ectopic expression of Chfr in cancer cells that normally do not express it results in downregulation of HDAC1, leading to upregulation of the Cdk inhibitor p21(CIP1/WAF1) and the metastasis suppressors KAI1 and E-cadherin. Coincident with these changes, cells arrest in the G1 phase of the cell cycle and become less invasive. Collectively, our data suggest that Chfr functions as a tumour suppressor by regulating HDAC1.
Chfr是一种泛素连接酶，通过响应有丝分裂应激延迟进入中期而在有丝分裂检查点发挥作用。有人提出Chfr是一种肿瘤抑制因子，因为Chfr在人类癌症中经常沉默。为了更好地理解Chfr活性与细胞周期进程和肿瘤发生的关系，我们试图通过亲和纯化结合质谱法鉴定与Chfr相互作用的蛋白质。组蛋白去乙酰化酶1（HDAC1），通过使组蛋白去乙酰化来抑制转录，被新分离为一种与Chfr相互作用的蛋白质。Chfr在体外和体内通过诱导HDAC1的多聚泛素化来结合并下调HDAC1。在通常不表达Chfr的癌细胞中异位表达Chfr会导致HDAC1下调，从而导致细胞周期蛋白依赖性激酶抑制剂p21（CIP1/WAF1）以及转移抑制因子KAI1和E-钙黏蛋白上调。与这些变化一致，细胞停滞在细胞周期的G1期且侵袭性降低。总体而言，我们的数据表明Chfr通过调节HDAC1发挥肿瘤抑制因子的作用。
