title: Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.
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.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Hee Min
authors.initials: HM
authors.lastname: Yoo
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Kang
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jae Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Departments of Internal Medicine, Surgery, and Neurology, College of Medicine, Seoul National University, Seoul 110-744, Korea.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Min Woo
authors.initials: MW
authors.lastname: Seong
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seong Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seung Hyeun
authors.initials: SH
authors.lastname: Ka
authors.affiliation: Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Sou
authors.affiliation: Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Departments of Internal Medicine, Surgery, and Neurology, College of Medicine, Seoul National University, Seoul 110-744, Korea.
authors.forename: Soon Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Departments of Internal Medicine, Surgery, and Neurology, College of Medicine, Seoul National University, Seoul 110-744, Korea.
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Noh
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea. Electronic address: gydbs98@snu.ac.kr.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea. Electronic address: chchung@snu.ac.kr.
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
mesh_terms: D027182:Amino Acid Transport System y+ / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D004958:Estradiol / Q000235:genetics / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D002352:Carrier Proteins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D011506:Proteins; C498799:SLC7A10 protein, human; C502095:UBA5 protein, human; C502094:UFM1 protein, human; C560260:UFM1-binding protein 1 containing a PCI domain, mouse; D025801:Ubiquitin; D013629:Tamoxifen; D004958:Estradiol; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D044764:Ubiquitin-Activating Enzymes; C587954:UFL1 protein, human