Modification of ERα by UFM1 Increases Its Stability and Transactivity for Breast Cancer Development

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.

Inhibition of UFM1 expression suppresses cancer progression and is linked to the dismal prognosis and immune infiltration in oral squamous cell carcinoma

“…Studies have displayed that some biomarkers could predict the prognosis of OSCC patients, and inhibiting or promoting their expression could cause tumor growth arrest [2,5,14]. Several studies have reported the association of UFM1 with prognosis in GC, HCC, and breast cancer patients [7][8][9][10]. Currently, the role of UFM1 in OSCC has not been revealed.…”

“…AGING Ubiquitin Fold Modifier 1 (UFM1) is a ubiquitin-like protein that could be coupled to the target protein like ubiquitination through the E1-like activating enzyme UBA5 and E2-like coupling enzyme UFC1 [6]. Previous studies confirmed that the changes in UFM1 expression were related to the progression of gastric cancer (GC), hepatocellular carcinoma (HCC), and breast cancer [7][8][9][10]. For example, the levels of UFM1 were down-regulated in GC tissues.…”

The UFM1 conjugation system in mammalian development

“…Histone 4 is also UFMylated following DNA damage to maintain genomic integrity 16,17 . P53, P4HB, and ERα can all be UFMylated to antagonize degradation via the ubiquitin–proteasome pathway 10,18,19 …”

“…16,17 P53, P4HB, and ERα can all be UFMylated to antagonize degradation via the ubiquitin-proteasome pathway. 10,18,19 It has been proposed that most UFMylation components reside in the ER. UFL1, UFSP2, UFBP1, and CDK5RAP3 have all been shown to aggregate in a large protein complex at the cytosolic side of the ER membrane.…”

DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination

“…[ 20 ] Furthermore, by interacting with activating signal cointegrator 1 (ASC1), DDRGK1 regulates ASC1 UFMylation and promotes ER‐positive breast cancer development. [ 21 ] However, DDRGK1 has also been shown to maintain p53 stability and impair the growth of colon cancer via cooperation with UFM1 and covalent modification of p53. [ 22 ] Without further research, it is difficult to fully characterize the function of DDRGK1 in tumors.…”