Chfr is linked to tumour metastasis through the downregulation of HDAC1

Article metrics

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Kang, D., Chen, J., Wong, J. & Fang, G. The checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition. J. Cell Biol. 156, 249–259 (2002).

  2. 2

    Yu, X. et al. Chfr is required for tumor suppression and Aurora A regulation. Nature Genet. 37, 401–406 (2005).

  3. 3

    Scolnick, D. M. & Halazonetis, T. D. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature 406, 430–435 (2000).

  4. 4

    Bothos, J., Summers, M. K., Venere, M., Scolnick, D. M. & Halazonetis, T. D. The Chfr mitotic checkpoint protein functions with Ubc13–Mms2 to form Lys 63-linked polyubiquitin chains. Oncogene 22, 7101–7107 (2003).

  5. 5

    Chaturvedi, P. et al. Chfr regulates a mitotic stress pathway through its RING-finger domain with ubiquitin ligase activity. Cancer Res. 62, 1797–1801 (2002).

  6. 6

    Oh, Y. M., Yoo, S. J. & Seol, J. H. Deubiquitination of Chfr, a checkpoint protein, by USP7/HAUSP regulates its stability and activity. Biochem. Biophys. Res. Commun. 357, 615–619 (2007).

  7. 7

    Matsusaka, T. & Pines, J. Chfr acts with the p38 stress kinases to block entry to mitosis in mammalian cells. J. Cell Biol. 166, 507–516 (2004).

  8. 8

    Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).

  9. 9

    Tsai, M. D. FHA: a signal transduction domain with diverse specificity and function. Structure 10, 887–888 (2002).

  10. 10

    Stavridi, E. S. et al. Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein and its complex with tungstate. Structure 10, 891–899 (2002).

  11. 11

    Wang, A. G. et al. Histone deacetylase 1 contributes to cell cycle and apoptosis. Biol. Pharm. Bull. 28, 1966–1970 (2005).

  12. 12

    Kim, J. H. et al. Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes. Nature 434, 921–926 (2005).

  13. 13

    David, G., Neptune, M. A. & DePinho, R. A. SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J. Biol. Chem. 277, 23658–23663 (2002).

  14. 14

    Ito, A. et al. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 21, 6236–6245 (2002).

  15. 15

    Ocker, M. & Schneider-Stock, R. Histone deacetylase inhibitors: signalling towards p21cip1/waf1. Int. J. Biochem. Cell Biol. 39, 1367–1374 (2007).

  16. 16

    Li, H. & Wu, X. Histone deacetylase inhibitor, trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-Myc and release of the repression of c-Myc from the promoter in human cervical cancer cells. Biochem. Biophys. Res. Commun. 324, 860–867 (2004).

  17. 17

    Senese, S. et al. Role for histone deacetylase 1 in human tumor cell proliferation. Mol. Cell. Biol. 27, 4784–4795 (2007).

  18. 18

    Mizuno, K. et al. Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers. Oncogene 21, 2328–2333 (2002).

  19. 19

    Brandes, J. C., van Engeland, M., Wouters, K. A., Weijenberg, M. P. & Herman, J. G. CHFR promoter hypermethylation in colon cancer correlates with the microsatellite instability phenotype. Carcinogenesis 26, 1152–1156 (2005).

  20. 20

    Privette, L. M., Gonzalez, M. E., Ding, L., Kleer, C. G. & Petty, E. M. Altered expression of the early mitotic checkpoint protein, CHFR, in breast cancers: implications for tumor suppression. Cancer Res. 67, 6064–6074 (2007).

  21. 21

    Cheng, C. W. et al. Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene. Oncogene 20, 3814–3823 (2001).

  22. 22

    Yang, J. Y. et al. MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation. Mol. Cell. Biol. 26, 7269–7282 (2006).

  23. 23

    Kim, J. H. et al. Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis. Nature Cell Biol. 8, 631–639 (2006).

  24. 24

    Baker, D. J., Chen, J. & van Deursen, J. M. The mitotic checkpoint in cancer and aging: what have mice taught us? Curr. Opin. Cell Biol. 17, 583–589 (2005).

  25. 25

    Cao, R., Tsukada, Y. & Zhang, Y. Role of Bmi-1 and Ring21A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 20, 845–854 (2005).

Download references

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.

Author information

Correspondence to Jae Hong Seol.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1264 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading