SIRT5 Promotes Cisplatin Resistance in Ovarian Cancer by Suppressing DNA Damage in a ROS-Dependent Manner via Regulation of the Nrf2/HO-1 Pathway.

Xiaodan Sun,Shouhan Wang,Jingqian Guan,Yizhuo Li,Qingchang Li,Jinming Zhao,Chen Zhao,Lin Fu,Junda Gai,Ji Li

doi:10.3389/fonc.2019.00754

Abstract

Sirtuin 5 (SIRT5), a mitochondrial class III NAD-dependent deacetylase, plays controversial roles in tumorigenesis and chemoresistance. Accordingly, its role in ovarian cancer development and drug resistance is not fully understood. Here, we demonstrate that SIRT5 is increased in ovarian cancer tissues compared to its expression in normal tissues and this predicts a poor response to chemotherapy. SIRT5 levels were also found to be higher in cisplatin-resistant SKOV-3 and CAOV-3 ovarian cancer cells than in cisplatin-sensitive A2780 cells. Furthermore, this protein was revealed to facilitate ovarian cancer cell growth and cisplatin-resistance in vitro. Mechanistically, we show that SIRT5 contributes to cisplatin resistance in ovarian cancer by suppressing cisplatin-induced DNA damage in a reactive oxygen species (ROS)-dependent manner via regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.

Highlights

Sirtuin 5 (SIRT5) is a unique member of the Sirtuin family (Sirt1–7), which possesses multiple enzymatic activities including NAD-dependent histone deacetylase [1], potent lysine demalonylase, lysine desuccinylase [2], and lysine glutarylase [3] activities
The levels of γ-H2AX were suppressed when BRCA1 was upregulated upon overexpression of SIRT5, and they were increased after downregulation of BRCA1 upon knockdown of SIRT5 (Figure 5H)
Among the Sirtuin family, SIRT5 was highly expressed in ovarian cancer compared to its expression in normal tissues, based on the Gene Expression Profiling Interactive Analysis (GEPIA) database and this result was verified by immunohistochemistry

Summary

Introduction

SIRT5 is a unique member of the Sirtuin family (Sirt1–7), which possesses multiple enzymatic activities including NAD-dependent histone deacetylase [1], potent lysine demalonylase, lysine desuccinylase [2], and lysine glutarylase [3] activities. These specific enzymatic activities indicate that SIRT5 plays a crucial role in regulating multiple cellular metabolic processes such as glycolysis, the tricarboxylic acid cycle, fatty acid oxidation, nitrogen metabolism, and the pentose phosphate pathway [4, 5].

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Results

Conclusion