Ufmylation of ASC1 Is Essential for Breast Cancer Development

Aberrant activation of the nuclear receptor estrogen receptor α (ERα) drives tumor progression in nearly 70% of patients with breast cancer. The ERα binding partner activating signal cointegrator 1 (ASC1, also known as TRIP4) serves as a scaffold for the binding of nuclear receptors, transcriptional coactivators, and general transcriptional machinery; however, the mechanisms that regulate binding of the ASC1 zinc finger (ZF) domain to multiple factors during transcription remain unclear. Yoo and colleagues identified ASC1 as a target of posttranslational modification by the ubiquitin-like protein ubiquitin-fold modifier 1 (UFM1). This modification, known as ufmylation, required interaction of ASC1 with UFM1-binding protein and formation of lysine 69-linked poly-UFM1 chains at four lysine residues in ASC1. Ufmylation was reversed by expression of UFM1-specific protease 2 (UFSP2), which bound the ZF domain of ASC1, and knockdown of UFSP2 or deletion of the ASC1 ZF domain increased ASC1 ufmylation. Intriguingly, treatment with the ERα ligand 17β-estradiol (E₂) was necessary for ASC1 ufmylation; in the presence of E₂, ERα displaced UFSP2 and interacted with the ASC1 ZF domain, resulting in enhanced ASC1 ufmylation in ERα-positive breast cancer cells. Expression of wild-type, but not ufmylation-deficient, ASC1 promoted recruitment of transcriptional cofactors to ER-responsive elements in ERα target gene promoters and stimulated expression of these genes in response to E₂, supporting the hypothesis that ufmylation of ASC1 is required for efficient transactivation of the ERα transcriptional program. Furthermore, depletion of UFSP2 or overexpression of wild-type, but not ufmylation-deficient, ASC1 significantly enhanced ERα-positive breast cancer cell growth and xenograft tumor formation in response to E₂. Together, these findings demonstrate a critical role for ufmylation of ASC1 in ERα-positive breast cancer and suggest that components of the ufmylation machinery may represent potential therapeutic targets in patients with ERα-positive tumors.

Yoo HM, Kang SH, Kim JY, Lee JE, Seong MW, Lee SW, et al. Modification of ASC1 by UFM1 Is Crucial for ERα Transactivation and Breast Cancer Development. Mol Cell 2014 Sep 11 [Epub ahead of print].