Abstract
Sirtuins (SIRTs) 1–7 are a family of intracellular enzymes, which possess nicotinamide adenine dinucleotide-dependent deacetylase activity. Emerging evidence suggest that SIRTs play vital roles in tumorigenesis by regulating energy metabolism, DNA damage repair, genome stability, and other cancer-associated cellular processes. However, the distinct roles of the seven members in ovarian cancer (OC) remain elusive. The transcriptional expression patterns, prognostic values, and genetic alterations of seven SIRTs in OC patients were investigated in this study using a range of databases: Oncomine and Gene Expression Profiling Interactive Analysis, Kaplan–Meier plotter, the Cancer Genome Atlas, and cBioPortal. The protein–protein interaction networks of SIRTs were assessed in the String database. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway were analyzed in Database for Annotation, Visualization, and Integrated Discovery. The mRNA expression levels of SIRT1–4 and 7 were downregulated, while that of SIRT5 was upregulated and SIRT6 exhibited both expression dysregulation in patients with OC. Dysregulated SIRTs mRNA expression levels were associated with prognosis. Moreover, genetic alterations primarily occurred in SIRT2, 5, and 7. Network analysis indicated that SIRTs and their 20 interactors were associated with tumor-related pathways. This comprehensive bioinformatics analysis revealed that SIRT1–4, 6, and 7 may be new prognostic biomarkers, while SIRT5 is a potential target for accurate therapy for patients with OC, but further studies are needed to confirm this notion. These findings will contribute to a better understanding of the distinct roles of SIRTs in OC.
Highlights
Ovarian cancer (OC) ranked eighth in incidence and seventh in mortality rates globally among all cancers in women in 2018 (WHO, http://gco.iarc.fr/today/home)
Emerging evidence suggest that SIRTs play vital roles in tumorigenesis by regulating energy metabolism, DNA damage repair, genome stability, and various other cancer-associated cellular processes
The mRNA expression levels of SIRT1 were significantly downregulated in patients with ovarian cancer (OC) in Bonome’s dataset (Bonome et al, 2008) with a log2 fold change of −1.866, while SIRT5 and SIRT7 were higher in ovarian serous adenocarcinoma in two another datasets (Yoshihara Ovarian and the Cancer Genome Atlas (TCGA) datasets; log2 fold changes, 1.929 and 1.626, respectively) (Yoshihara et al, 2009) than in normal ovarian tissues (Table 1, bold font)
Summary
Ovarian cancer (OC) ranked eighth in incidence and seventh in mortality rates globally among all cancers in women in 2018 (WHO, http://gco.iarc.fr/today/home). The absence of incipient symptoms leads to over three quarters of patients being diagnosed at advanced stages (Zhou et al, 2018). Standard treatment for this disease involves surgical intervention combined with chemotherapy. Seven members (SIRT1–7) in mammals are divided into the following four classes: SIRT1–3, I; SIRT4, II; SIRT5, III; and SIRT6-7, IV (O’Callaghan and Vassilopoulos, 2017) Based on their subcellular localization, they can be categorized as follows: SIRT1, 6, and 7 reside in the nucleus; SIRT2 is expressed in both the nucleus and cytoplasm; and SIRT3, 4, and 5 are in the mitochondria (Chalkiadaki and Guarente, 2015). Aberrant expression of SIRTs has been found in common human carcinomas such as breast, lung, liver, and gastrointestinal cancers, as well as OC and neurologic tumors (Chen et al, 2013; Chalkiadaki and Guarente, 2015; Osborne et al, 2016; O’Callaghan and Vassilopoulos, 2017)
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