KMID : 0578320220450060425
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Molecules and Cells 2022 Volume.45 No. 6 p.425 ~ p.434
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Modification of ER¥á by UFM1 Increases Its Stability and Transactivity for Breast Cancer Development
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Yoo Hee-Min
Park Jong-Ho Kim Jae-Yeon Chung Chin-Ha
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Abstract
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The post-translational modification (e.g., phosphorylation) of estrogen receptor ¥á (ER¥á) plays a role in controlling the expression and subcellular localization of ER¥á as well as its sensitivity to hormone response. Here, we show that ER¥á is also modified by UFM1 and this modification (ufmylation) plays a crucial role in promoting the stability and transactivity of ER¥á, which in turn promotes breast cancer development. The elevation of ufmylation via the knockdown of UFSP2 (the UFM1-deconjugating enzyme in humans) dramatically increases ER¥á stability by inhibiting ubiquitination. In contrast, ER¥á stability is decreased by the prevention of ufmylation via the silencing of UBA5 (the UFM1-activating E1 enzyme). Lys171 and Lys180 of ER¥á were identified as the major UFM1 acceptor sites, and the replacement of both Lys residues by Arg (2KR mutation) markedly reduced ER¥á stability. Moreover, the 2KR mutation abrogated the 17¥â-estradiol-induced transactivity of ER¥á and the expression of its downstream target genes, including pS2, cyclin D1, and c-Myc; this indicates that ER¥á ufmylation is required for its transactivation function. In addition, the 2KR mutation prevented anchorage-independent colony formation by MCF7 cells. Most notably, the expression of UFM1 and its conjugating machinery (i.e., UBA5, UFC1, UFL1, and UFBP1) were dramatically upregulated in ER¥á-positive breast cancer cell lines and tissues. Collectively, these findings implicate a critical role attributed to ER¥á ufmylation in breast cancer development by ameliorating its stability and transactivity.
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KEYWORD
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breast cancer, estrogen receptor alpha, proteasome, transactivity, ubiquitin, ubiquitin-fold modifier 1
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