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Review
. 2020 Nov;20(5):162.
doi: 10.3892/ol.2020.12023. Epub 2020 Aug 26.

Potential relationship between Sirt3 and autophagy in ovarian cancer

Yuchuan Shi  1 , Runhua He  1 , Yu Yang  2 , Yu He  1 , Lei Zhan  1   3 , Bing Wei  1
Affiliations
Review

Potential relationship between Sirt3 and autophagy in ovarian cancer

Yuchuan Shi et al. Oncol Lett. 2020 Nov.

Abstract

Sirtuin 3 (Sirt3) is an important member of the sirtuin protein family. It is a deacetylase that was previously reported to modulate the level of reactive oxygen species (ROS) production and limit the extent of oxidative damage in cellular components. As an important member of the class III type of histone deacetylases, Sirt3 has also been documented to mediate nuclear gene expression, metabolic control, neuroprotection, cell cycle and proliferation. In ovarian cancer (OC), Sirt3 has been reported to regulate cellular metabolism, apoptosis and autophagy. Sirt3 can regulate autophagy through a variety of different molecular signaling pathways, including the p62, 5'AMP-activated protein kinase and mitochondrial ROS-superoxide dismutase pathways. However, autophagy downstream of Sirt3 and its association with OC remains poorly understood. In the present review, the known characteristics of Sirt3 and autophagy were outlined, and their potential functional roles were discussed. Following a comprehensive analysis of the current literature, Sirt3 and autophagy may either serve positive or negative roles in the regulation of OC. Therefore, it is important to identify the appropriate expression level of Sirt3 to control the activation of autophagy in OC cells. This strategy may prove to be a novel therapeutic method to reduce the mortality of patients with OC. Finally, potential research directions into the association between Sirt3 and other signaling pathways were provided.

Keywords: autophagy; ovarian cancer; sirtuin 3.

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Figures

Figure 1.
Figure 1.
Potential signaling pathways underlying Sirt3-mediated regulation of autophagy. Sirt3 is involved in autophagy via the downregulation of p62. The Sirt3/FOXO3a/p62 and macrophage stimulating 1/Sirt3 signaling pathways can downregulate p62 expression. In addition, Sirt3 can directly activate PI3K/AKT signaling to inhibit autophagy. Mechanistically, Sirt3 indirectly controls the hyperactivation of AKT by regulating mitochondrial ROS production and ROS-mediated Ras-PI3K-AKT activation. Sirt3 can activate LKB1, such that the LKB1-AMPK-mTOR pathway serves an important role in autophagy. AMPK can inhibit mTOR directly to promote autophagy whilst also acting upstream of Sirt3. ROS can act as a trigger signal to induce autophagy through autophagy related protease 4. Autophagy may be suppressed by Sirt3 through the regulation of mitochondrial ROS production. The Sirt3/SOD2 pathway is involved in mitochondrial-derived O2-stimulated autophagic cell death. Sirt3-mediated deacetylation can significantly increase the activity of SOD2 to ultimately reduce intracellular ROS levels. Sirt3, sirtuin; FOXO3a, forkhead box O3; ROS, reactive oxygen species; LKB1, liver kinase B1; AMPK, 5′AMP-activated protein kinase; SOD2, superoxide dismutase 2.
Figure 2.
Figure 2.
Relationship between Sirt3 and autophagy in ovarian cancer. Metformin-induced overexpression of Sirt3 activates AMPK, which in turn increases the expression of LC3. This results in the elevation in the expression of proteins associated with cell migration, such as MTA1. S1 is a novel pan Bcl-2 inhibitor that has been documented to activate autophagy by interrupting the interaction between Bcl-2 and Beclin1. Sirt3 is involved in the regulation of autophagy via the GTSP1/JNK/autophagy pathway. S1 can promote the expression of JNK3. Knocking down Sirt3 expression can alleviate S1-induced apoptosis. MTA1, metastasis-associated protein; GTSP, glutathione S-transferase P; LC3, microtubule-associated proteins 1A/1B light chain 3B; Sirt3, sirtuin; AMPK, 5′AMP-activated protein kinase.
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