FAT10 promotes the invasion and migration of breast cancer cell through stabilization of ZEB2

Highlights

• High FAT10 level was closely associated with the malignant phenotype and shorter survival in the BC patients.

• FAT10 knockdown suppressed the metastasis abilities and the EMT of breast cancer cell.

• FAT10 directly interacts with ZEB2 and stabilizes its expression in breast cancer cells.

• The pro-metastasis role of FAT10 in breast cancer is dependent on ZEB2 enhancement.

Abstract

FAT10, an ubiquitin-like protein, functions as a potential tumor promoter in several caners. However, the function and clinical significance of FAT10 in breast cancer (BC) remains unclear. Here, we found that high FAT10 expression was detected frequently in primary BC tissues, and was closely associated with malignant phenotype and shorter survival among the BC patients. Multivariate analyses also revealed that FAT10 overexpression was independent prognostic factors for poor outcome of patients with BC. Function assay demonstrated that FAT10 knockdown significantly inhibited the metastasis abilities and the epithelial-mesenchymal transition (EMT) of breast cancer cell. Further investigation revealed that FAT10 directly bound ZEB2 and decreased its ubiquitination to enhance the protein stability of ZEB2 in BC cells. Moreover, our data shown that the pro-metastasis effect of FAT10 in BC is partially dependent on ZEB2 enhancement. Collectively, our data suggest that FAT10 plays a crucial oncogenic role in BC metastasis, and we provide a novel evidence that FAT10 may be serve as a prognostic and therapeutic target for BC patients.

Introduction

Breast cancer (BC) is currently the most common form of cancer, and is the fifth leading cause of mortality among women worldwide [1,2]. With the advance of knowledge, breast cancer is clinically divided into three major molecular subtypes, including luminal, HER2-positive, and triple-negative breast cancer [3,4]; distant metastases are the cause of about 90% of deaths in patients with BC [5]. Thus, better understanding of the molecular mechanisms involved in BC metastasis may be helpful in developing therapeutic strategies for breast cancer.

Human Leukocyte Antigen (HLA)-F adjacent transcript 10 (FAT10), also known as Ubd, which is a member of the ubiquitin-like (UBL) modifier family and contains two UBL moieties fused in tandem [6,7]. Similar to other UBL proteins, FAT10 covalently modifies target substrates via a C-terminal Gly-Gly motif and has been involved in many cellular process [8,9]. Emerging evidence has identified FAT10 as a positive regulator of oncogenes and negative regulator of tumor suppressors in a variety of cancer types [[10], [11], [12], [13]]. For instance, high expression of FAT10 notably correlates with metastasis and indicates poor prognosis in hepatocellular carcinoma [12]. However, the clinical significance and potential role of FAT10 in breast cancer is largely unknown.

Here, we found that high FAT10 level is closely related with progression and poor outcome of patients with breast cancer. Further, our results showed that knockdown of FAT10 dramatically suppressed the migration, invasion and EMT of breast cancer cells. Moreover, we confirmed that FAT10 directly interacted with zinc finger E-box binding homeobox 2 (ZEB2), a crucial repressor of EMT progression in diverse cancers including BC [[14], [15], [16]], and decreased its ubiquitination to enhance the protein stability of ZEB2 in BC cells. Thus, FAT10 may become a new therapeutic target or clinical biomarker for metastatic breast cancer.