Modification of ASC1 by UFM1 Is Crucial for ERα Transactivation and Breast Cancer Development

• DOI: 10.1016/j.molcel.2014.08.007
• Publication Date: 2014-09-11T16:48:25Z
• Authors: Hee Min Yoo; Sung Hwan Kang; Jae Yeon Kim; Joo Eun Lee; Min Woo Seong; Seong Won Lee; Seung Hyeun Ka; Yu-Shin Sou; Masaaki Komatsu; Keiji Tanaka; Soon Tae Lee; Dong Young Noh; Sung Hee Baek; Young Joo Jeon; Chin Ha Chung
• Keywords: 0301 basic medicine; Amino Acid Transport System y+; Mice, Nude; Breast Neoplasms; Mice; 03 medical and health sciences; Nuclear Receptor Coactivator 1; Cell Line, Tumor; Animals; Humans; Promoter Regions, Genetic; Molecular Biology; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Cell Biology; 3. Good health; Enzyme Activation; Cysteine Endopeptidases; HEK293 Cells; MCF-7 Cells; Female; Carrier Proteins; E1A-Associated p300 Protein; Protein Binding

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.