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Chfr is linked to tumour metastasis through the downregulation of HDAC1

Nature Cell Biology volume 11, pages 295–302 (2009)Cite this article

Abstract

Chfr is a ubiquitin ligase that functions in the mitotic checkpoint by delaying entry into metaphase in response to mitotic stress1,2. It has been suggested that Chfr is a tumour suppressor as Chfr is frequently silenced in human cancers3. 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 p21CIP1/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.

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Figure 1: Chfr interacts with HDAC1 directly.
Figure 2: The C-terminal CR region of Chfr is required for its interaction with HDAC1.
Figure 3: Chfr negatively regulates and ubiquitylates HDAC1 in vitro and in vivo.
Figure 4: Chfr stimulates the p21 transcription that was repressed by HDAC1.
Figure 5: Chfr modulates the invasive activity of metastatic cancer cells.

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Acknowledgements

We thank S. H. Baek (SNU) for reagents. This work was supported by grants from the Korea Science and Engineering Foundation (M10533010001-07N3301-00110), the SRC program (R11-2005-009-02002-0), the Korea Research Foundation (KRF-2002-015-CS0069) and the BK21 program. Y.E.K. was supported by the Seoul Science Fellowship.

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Authors and Affiliations

  1. School of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul, 151-742, Korea

    Young Mi Oh, Young Eun Kwon, Joo Mi Kim, Sung Jun Bae, Bo Keun Lee, Chin Ha Chung & Jae Hong Seol

  2. Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Seoul, 130-701, Korea

    Soon Ji Yoo

  3. Division of Biology, California Institute of Technology, Pasadena, 91125, CA, USA

    Raymond J. Deshaies

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Correspondence to Jae Hong Seol.

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Oh, Y., Kwon, Y., Kim, J. et al. Chfr is linked to tumour metastasis through the downregulation of HDAC1. Nat Cell Biol 11, 295–302 (2009). https://doi.org/10.1038/ncb1837

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