Chfr is linked to tumour metastasis through the downregulation of HDAC1.
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.
Oh
Young Mi
YM
School of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul 151-742, Korea.
Kwon
Young Eun
YE
Kim
Joo Mi
JM
Bae
Sung Jun
SJ
Lee
Bo Keun
BK
Yoo
Soon Ji
SJ
Chung
Chin Ha
CH
Deshaies
Raymond J
RJ
Seol
Jae Hong
JH
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000473:pathology*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012097:Repressor Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases