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

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

doi:10.1016/j.molcel.2014.08.007

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

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

Authors

Affiliations

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.

PMID: 25219498
DOI: 10.1016/j.molcel.2014.08.007

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport System y+ / chemistry
Amino Acid Transport System y+ / genetics
Amino Acid Transport System y+ / metabolism*
Animals
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Carrier Proteins / metabolism
Cell Line, Tumor
Cysteine Endopeptidases / metabolism
E1A-Associated p300 Protein / genetics
Enzyme Activation / genetics
Estradiol / genetics
Estradiol / metabolism
Estrogen Antagonists / pharmacology
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism*
Female
HEK293 Cells
Humans
MCF-7 Cells
Mice
Mice, Nude
Nuclear Receptor Coactivator 1 / genetics
Promoter Regions, Genetic / genetics
Protein Binding / genetics
Proteins / chemistry*
Proteins / metabolism
Tamoxifen / pharmacology
Transcriptional Activation
Ubiquitin / metabolism
Ubiquitin-Activating Enzymes / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

Amino Acid Transport System y+
Carrier Proteins
Estrogen Antagonists
Estrogen Receptor alpha
Proteins
SLC7A10 protein, human
UBA5 protein, human
UFM1 protein, human
UFM1-binding protein 1 containing a PCI domain, mouse
Ubiquitin
Tamoxifen
Estradiol
E1A-Associated p300 Protein
EP300 protein, human
NCOA1 protein, human
Nuclear Receptor Coactivator 1
Ubiquitin-Protein Ligases
Cysteine Endopeptidases
Ubiquitin-Activating Enzymes
UFL1 protein, human