내용요약(Abstract)
Estrogen receptor-a (ERa), a member of the nuclear receptor superfamily, is prominent in breast cancer. Upon binding of 17b-estradiol, ERa forms a dimeric complex, translocates to the nucleus, recruits transcriptional co-activators, and binds to the promoters of its target genes for transcriptional activation. Thus, ERa is known as a growth factor that is essential for proliferation of a large subset of breast tumor cells. Activating signal co-integrator 1 (ASC1) is a transcriptional co-activator of ERa and other nuclear receptors. ASC1 has a zinc-finger domain, which serves as a binding site for nuclear receptors, transcriptional co-activators, and basic transcriptional machinery. Thus, ASC1 plays a critical role as a platform that recruits the necessary components for nuclear receptor-mediated transcription.
Ubiquitin-fold modifier 1 (UFM1) is the most recently identified ubiquitin-like protein. Like ubiquitination, protein modification by UFM1 (ufmylation) utilizes a three-step enzyme system: UBA5 as an UFM1-activating E1 enzyme, UFC1 as an UFM1-conjugating E2 enzyme, and UFL1 as an UFM1 E3 ligase. Ufmylation process can be reversed by UFM1-specific proteases (UfSPs). In this study, we show that ASC1 ufmylation is crucial for breast cancer development. In the absence of 17b-estradiol, UfSP2 bound to ASC1 and prevented its ufmylation. In its presence, however, ERa displaced UfSP2 for its interaction with ASC1, leading to ASC1 ufmylation. Poly-UFM1 chains conjugated to ASC1 served as a scaffold that recruits p300, SRC1, and itself to the promoters of ERa target genes for transactivation. ASC1 overexpression or UfSP2 knockdown increased ERa-mediated tumor formation in vivo, and this increase could be abrogated by treatment with tamoxifen, an anti-breast cancer drug. In contrast, expression of the ufmylation-deficient ASC1 mutant or knockdown of UBA5 prevented the tumor growth. These findings establish the role of ASC1 ufmylation in breast cancer development via promotion of ERa transactivation.