Abstract
BackgroundSirtuins (SIRT1-7) are a family of NAD-dependent deacetylases, which play an important role in regulating cancer tumorigenesis; however, their role in oral cancer has been controversial. SIRT3 is localized in the mitochondria, where it deacetylates and activates several enzymes involved in cellular redox balance and defense against oxidative damage.ResultsWe found that compared with normal human oral keratinocytes (HOK), SIRT3 is highly expressed in oral squamous cell carcinoma (OSCC) cell lines, but the enzymatic deacetylation is significantly reduced. We also sequenced the entire coding region of SIRT3 and found the same mutation in 2 different OSCC cell lines. This point mutation is located in close proximity to the active site of deacetylase in the SIRT3 protein, and reduces the overall enzymatic efficiency of deacetylation. Furthermore, up-regulation of SIRT3 inhibited the cell growth of OSCCs and decreased the levels of basal reactive oxygen species (ROS) in both OSCC lines. To verify that the SIRT3 sequence variation was associated with oral carcinogenesis, we sequenced the SIRT3 gene from 21 OSCC patients, and 5 of the 21 patients (23.8%) carried the heterozygous missense mutation, p.Val208Ile. The heterozygous missense mutation in these patients was present in gremlin DNA isolated from both normal and tumor tissues.ConclusionsOur findings provide a valuable insight into the potential role of SIRT3 in the development of oral squamous cell carcinoma, by showing that a non-synonymous point mutation in SIRT3 contributes to reduced catalytic activity of the protein and affects redox balance in OSCCs.
Highlights
Sirtuins (SIRT1-7) are a family of Nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, which play an important role in regulating cancer tumorigenesis; their role in oral cancer has been controversial
Variable levels of SIRT3 expression and its activity To examine whether expression of SIRT3 was different between normal primary human oral keratinocytes (HOK) and Oral squamous cell carcinoma (OSCC), we examined the mRNA and protein levels in 2 OSCC cell lines (HSC-3 and OECM1) and compared those cells with HOK cells (Figure 1A)
We found that SIRT3 was slightly overexpressed in both OSCC cell lines compared to expression in HOK, the SIRT3 mRNA levels were lower in OSCC cell lines
Summary
Sirtuins (SIRT1-7) are a family of NAD-dependent deacetylases, which play an important role in regulating cancer tumorigenesis; their role in oral cancer has been controversial. SIRT3 overexpression in vivo suppresses cellular ROS levels [29] These SIRT3−/− mice display higher rates of high fat dietinduced obesity, insulin resistance, hyperlipidemia, and steatohepatitis [32]. In accordance with the studies, cells lacking SIRT3 may have dysfunctional coordination of both mitochondrial respiratory chain and detoxification enzymes, which can result in aberrant and potentially damaging levels of ROS. This suggests that SIRT3 may regulate the initiation and progression of cancer by controlling the cellular redox balance. The objective of the current study was to elucidate the role of SIRT3 in regulating cellular redox balance in OSCC
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