Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer

Abstract

Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, may target mitochondrial proteins for lysine deacetylation and also regulate cellular functions. And, SIRT3 is an emerging instrumental regulator of the mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. Accumulating evidence has recently demonstrated that SIRT3 may function as either oncogene or tumor suppressor on influencing cell death by targeting a series of key modulators and their relevant pathways in cancer. Thus, in this review, we present the structure, transcriptional regulation, and posttranslational modifications of SIRT3. Subsequently, we focus on highlighting the Janus role of SIRT3 with oncogenic or tumor-suppressive function in cancer, which may provide more new clues for exploring SIRT3 as a therapeutic target for drug discovery.

Figure 1

SIRT3 structure with its activators and inhibitors. SIRT3 is a soluble protein located in the mitochondrial matrix, containing a mitochondrial processing peptide at the N-terminus, with a conserved enzymatic core with two domains. Moreover, several SIRT3 activators (resveratrol and oroxylin A) and novel SIRT3 inhibitor 5-amino-2-phenyl-benzoxazole have also been reported

Figure 2

SIRT3 and the hallmarks of cancer. SIRT3 can link to six hallmarks of cancer, such as resisting cell death, genomic instability and mutation, sustaining proliferative signaling, dysregulation of cellular energetics, tumor-promoting inflammation and invading growth suppressors

Figure 3

SIRT3 in cancer cell. SIRT3 can limit ROS levels in cancer cell, thereby leading to the destabilization and subsequent degradation of HIF-1α. Moreover, SIRT3 overexpression may prevent intracellular acidification, Bax activation and MPT induction

Figure 4

SIRT3 has as an oncogenic or a tumor-suppressive role in cancer