Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Modification of ERα by UFM1 Increases Its Stability and Transactivity for Breast Cancer Development

  • Yoo, Hee Min (School of Biological Sciences, Seoul National University) ;
  • Park, Jong Ho (School of Biological Sciences, Seoul National University) ;
  • Kim, Jae Yeon (School of Biological Sciences, Seoul National University) ;
  • Chung, Chin Ha (School of Biological Sciences, Seoul National University)
  • Received : 2022.02.22
  • Accepted : 2022.03.14
  • Published : 2022.06.30
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Abstract

The post-translational modification (e.g., phosphorylation) of estrogen receptor α (ERα) plays a role in controlling the expression and subcellular localization of ERα as well as its sensitivity to hormone response. Here, we show that ERα is also modified by UFM1 and this modification (ufmylation) plays a crucial role in promoting the stability and transactivity of ERα, which in turn promotes breast cancer development. The elevation of ufmylation via the knockdown of UFSP2 (the UFM1-deconjugating enzyme in humans) dramatically increases ERα stability by inhibiting ubiquitination. In contrast, ERα stability is decreased by the prevention of ufmylation via the silencing of UBA5 (the UFM1-activating E1 enzyme). Lys171 and Lys180 of ERα were identified as the major UFM1 acceptor sites, and the replacement of both Lys residues by Arg (2KR mutation) markedly reduced ERα stability. Moreover, the 2KR mutation abrogated the 17β-estradiol-induced transactivity of ERα and the expression of its downstream target genes, including pS2, cyclin D1, and c-Myc; this indicates that ERα 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 ERα-positive breast cancer cell lines and tissues. Collectively, these findings implicate a critical role attributed to ERα ufmylation in breast cancer development by ameliorating its stability and transactivity.

Keywords

Acknowledgement

We thank Dong-Young Noh for providing human breast cancer tissues. This work was supported by National Academy of Sciences, ROK and National Research Foundation of Korea (NRF-2005-084-C00025) to C.H.C. and by Korea Research Institute of Standards and Science ("Establishment of measurement standards for Chemistry and Radiation," KRISS-2022-GP2022-0003), the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2016M3A7B6908929, NRF-2019M3A9F3065868, and NRF-2021M3C1C3097638) to H.M.Y. This study was approved by the Seoul National University Hospital (SNUH) Institutional Review Board (IRB) (approval No. 1207-119-420).

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