The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis.

Guangxian Lu,Xinyuan Ding,Jinhui Xu,Xin Liu,Lian Tang,Wenjuan Wang,Jiantong Sun,Qin Zhou,Jianhua Li,Leyun Ding,Chenping Wang

doi:10.3389/fonc.2021.629640

Abstract

Ubiquitin C-terminal hydrolase L1 (UCHL1), which is a deubiquitinating enzyme, is known to play a role in chemoresistance in cancers. However, its potential roles and mechanisms in the chemoresistance of breast cancer (BC) remain unclear. In this study, we examined its expression in patients with BC and employed Kaplan–Meier analysis and the log-rank test for survival analyses. It was found that up-regulated UCHL1 expression was positively associated with both chemoresistance and poor prognosis, especially in patients with HER2+ BC. Moreover, UCHL1 expression was elevated in HER2+ BC cells (SK-BR-3 and BT474). Similarly, doxorubicin (DOX)-resistant BC cells (MCF-7/DOX) had higher UCHL1 levels than MCF-7 cells. CCK-8 assay showed that BC cells with higher UCHL1 levels were more resistant to DOX. Furthermore, by inhibiting UCHL1 in BC cells with elevated UCHL1 expression, we demonstrated that UCHL1 promoted DOX-resistance in BC. Mechanistically, UCHL1 probably promoted DOX-resistance of BC by up-regulating free fatty acid (FFA) synthesis, as exhibited by reduced FFA synthase expression and resurrected DOX-sensitivity upon UCHL1 inhibition. Overall, UCHL1 up-regulation is associated with DOX-resistance and poor prognosis in patients with HER2+ BC. UCHL1 induces DOX-resistance by up-regulating FFA synthesis in HER2+ BC cells. Thus, UCHL1 might be a potential clinical target for overcoming DOX resistance in patients with HER2+ BC.

Highlights

Breast cancer (BC) is one of the most common cancers among women worldwide
To explore the role of Ubiquitin C-terminal hydrolase L1 (UCHL1) in DOX resistance in breast cancer (BC), we evaluated IHC and showed that UCHL1 was differentially expressed in 54 patients with BC (Figure 1A), with an IHC score cut-off value of 135, which was employed to classify
Patients with high UCHL1 expression showed a higher rate of resistance to clinical chemotherapy (Figure 1C), UCHL1 expression was not significantly associated with any other clinicopathological characteristics (Table 1)

Summary

Introduction

Breast cancer (BC) is one of the most common cancers among women worldwide. BC is classified into three categories depending on clinical and histopathological characteristics and the expression of progesterone receptor (PR), estrogen receptor (ER), human epidermal growth factor receptor 2related protein (HER2), and Ki67 [2]. The HER2-positive (HER2+) subtype exists in UCHL1 promotes DOX-resistance in BC about 20% of patients with BC; it is associated with high risk and is a significant poor prognostic factor in clinical therapy [3]. Doxorubicin (DOX) is one of the most common first-line chemotherapy in the clinical treatment of early and advanced BC. DOX resistance often occurs in clinical practice, which limits long-term treatment benefits in these patients [6]

Methods

Results

Conclusion