Chfr is linked to tumor metastasis through the downregulation of HDAC1

Young Mi Oh, Young Eun Kwon, Joo Mi Kim, Sung Jun Bae, Bo Keun Lee, Soon Ji Yoo,

Chin Ha Chung, Raymond J. Deshaies and Jae Hong Seol.

Nat Cell Biol, Vol. 11, 295-302, 2009.

Speaker: Yu-Fen Tseng (曾鈺芬)                                  Time: 13:10~14:00, Oct. 21, 2009

Commentator: Dr. Shu-Ying Wang (王淑鶯博士)       Place: Room 601

Abstract:

Chfr is an ubiquitin ligase that functions as a mitotic checkpoint by delaying entry into metaphase in response to mitotic stress ¹. It has been reported that Chfr is downregulated in some cancer cells. Histone deacetylase1 (HDAC1) represses transcription of target genes in cell cycle, cell proliferation, and metastasis ^2 3. The authors identified HDAC1 as the Chfr-interacting protein by affinity purification followed by Liquid chromatography- mass spectrometry. They revealed that the C-terminal cysteine region of (CR) Chfr is required for its interaction with HDAC1 directly. They also showed that a part of the C‑terminal region of the HDAC1 deacetylase is involved in its interaction with Chfr. In addition, Chfr possesses ubiquitin ligase activity, and is able to ubiquitylate HDAC1 which binds to its CR domain of Chfr, resulting in proteasomal degradation of HDAC1. HDAC1 binds to the cyclin-dependent kinase inhibitor p21 ^cip1/waf1 through the Sp1 site on the p21 ^cip1/waf1 promoter and suppresses p21 activity ². Chfr activates p21 expression by repressing HDAC1 and causes p21-dependent cell cycle arrest in G1 phase. Furthermore, over-expression of Chfr, knockdown of HDAC1 or treatment with TSA decreased the invasive ability of MCF-7 cells by Matrigel invasion assay. Collectively, they demonstrated that Chfr functions as a tumor suppressor by regulating HDAC1.

References:

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

2.         Wang, A.G. et al. Histone deacetylase 1 contributes to cell cycle and apoptosis. Biological & pharmaceutical bulletin 28, 1966-1970 (2005).

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