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Mol Cell. 2014 Oct 23;56(2):261-274. doi: 10.1016/j.molcel.2014.08.007. Epub 2014 Sep 11.

Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.

Author information

1
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
2
Departments of Internal Medicine, Surgery, and Neurology, College of Medicine, Seoul National University, Seoul 110-744, Korea.
3
Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
4
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea. Electronic address: gydbs98@snu.ac.kr.
5
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea. Electronic address: chchung@snu.ac.kr.

Abstract

Biological roles for UFM1, a ubiquitin-like protein, are largely unknown, and therefore we screened for targets of ufmylation. Here we show that ufmylation of the nuclear receptor coactivator ASC1 is a key step for ERα transactivation in response to 17β-estradiol (E2). In the absence of E2, the UFM1-specific protease UfSP2 was bound to ASC1, which maintains ASC1 in a nonufmylated state. In the presence of E2, ERα bound ASC1 and displaced UfSP2, leading to ASC1 ufmylation. Polyufmylation of ASC1 enhanced association of p300, SRC1, and ASC1 at promoters of ERα target genes. ASC1 overexpression or UfSP2 knockdown promoted ERα-mediated tumor formation in vivo, which could be abrogated by treatment with the anti-breast cancer drug tamoxifen. In contrast, expression of ufmylation-deficient ASC1 mutant or knockdown of the UFM1-activating E1 enzyme UBA5 prevented tumor growth. These findings establish a role for ASC1 ufmylation in breast cancer development by promoting ERα transactivation.

PMID:
25219498
DOI:
10.1016/j.molcel.2014.08.007
[Indexed for MEDLINE]
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