Sirt3 inhibits hepatocellular carcinoma cell growth through reducing Mdm2-mediated p53 degradation

Sirt3 is a member of the mammalian sirtuin family that is localized to mitochondria and plays a role in the control of the metabolic activity. Recently, Sirt3 has been reported to be associated with the deregulating metabolism of cancer cells. However, the role of Sirt3 in hepatocellular carcinoma (HCC) has never been studied. In this study, we found that Sirt3 protein expression was downregulated in human HCC tissue. We also showed that overexpression of Sirt3 using adenovirus inhibited HCC cell growth (two cell lines: HepG2 and HuH-7 cells) and induced apoptosis, which was evidenced by the increase of LDH leakage, enhancement of TUNEL-positive cells number and promotion of AIF translocation to nuclei. Sirt3 overexpression reduced the intracellular NAD+ level, repressed the ERK1/2 signaling pathway, and activated the Akt and JNK signaling pathways. Furthermore, Sirt3 overexpression upregulated p53 protein level through downregulating Mdm2 and thereby slowing p53 degradation. Collectively, our data suggests that Sirt3 may play an important role in HCC development and progression and may be a promising therapeutic target for HCC.

► Sirt3 protein level was downregulated in human hepatocellular carcinoma (HCC) tissue.
► Sirt3-overexpression (Sirt3-OE) inhibited HCC cell growth and induced apoptosis.
► Sirt3-OE modulated NAD+ level, ERK, p38 and JNK pathways in HCC cells.
► Sirt3-OE upregulated p53 protein through downregulating Mdm2 to slow p53 degradation.