UFM1 in the Control of ERα Transcriptional Activity

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講演要旨

Estrogen receptor-α (ERα), a member of the nuclear receptor superfamily, is prominent in breast cancer. Upon binding of estrogen, ERα forms a dimeric complex, translocates into the nucleus, recruits transcriptional co-activators, and binds to the promoters of its target genes for transcriptional activation. Ubiquitin-fold modifier 1 (UFM1) is the most recently identified ubiquitin-like protein. Like ubiquitination, protein modification by UFM1 (ufmylation) utilizes a three-step cascade 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). Previously, we have shown that poly-UFM1 chains conjugated to ASC1 (a transcriptional co-activator) play a crucial role in breast cancer development by serving as a scaffold that recruits p300, SRC1, and itself to the promoters of ERα target genes for transactivation. In this study, we show that ERαis also ufmylated and this modification promotes its transactivity by preventing E6AP-mediated ubiquitination. Ufmylation-deficient ERα mutant, unlike its wild-type form, could not promote estrogen-mediated anchorage-independent cell growth and tumor formation in vivo. These findings indicate that ERα ufmylation plays a crucial role in breast cancer development by temporal stabilization of the receptor.