Ubiquitin-fold modifier 1 acts as a positive regulator of breast cancer

Abstract

Estrogen receptor-α (ERα) is a steroid hormone-sensitive transcription factor that plays a critical role in development of breast cancer. The binding of estrogen to ERα triggers the recruitment of transcriptional co-activators as well as chromatin remodeling factors to estrogen-responsive elements (ERE) of ERα target genes. This process is tightly associated with post-translational modifications (PTMs) of ERα and its co-activators for promotion of transcriptional activation, which leads to proliferation of a large subset of breast tumor cells. These PTMs include phosphorylation, acetylation, methylation, and conjugation by ubiquitin and ubiquitin-like proteins. Ubiquitin-fold modifier 1 (UFM1), one of ubiquitin-like proteins, has recently been shown to be ligated to activating signal co-integrator 1 (ASC1), which acts as a transcriptional co-activator of nuclear receptors. Here, we discuss the mechanistic connection between ASC1 modification by UFM1 and ERα transactivation, and highlight how the interplay of these processes is involved in development of breast cancer. We also discuss potential use of UFM1-conjugating system as therapeutic targets against not only breast cancer but also other nuclear receptor-mediated cancers.

Keywords: ASC1; ERα; UFM1; breast cancer; post-translational modification.

Figure 1

3D structures of ubiquitin and UFM1 in human. PDB IDs for ubiquitin and UFM1 are 1UBQ and 1WXS, respectively.

Figure 2

Pathway for protein modification by UFM1. Matured UFM1 generated from its precursor by UFSP2 is activated by UBA5 (E1), transferred to UFC1 (E2), and then conjugated to target substrates by UFL1 (E3) with the aid of UFBP1. This ufmylation pathway can be reversed by USFP2. “S ~” indicates the thioester bond.

Figure 3

Schematic diagram for primary structures of UFBPs. “C” and “DPH” denote the active site Cys-box (red) and Asp-Pro-His box (orange), respectively. Note that hUFSP1 lacks the Cys box.

Figure 4

Pathway for estrogen-induced ASC1 ufmylation for ERα transactivation. “DRUG” indicates any small molecule that can act as a therapeutic anti-breast cancer drug by blocking ASC1 ufmylation.