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Review
. 2024 Oct 14;14(17):6726-6767.
doi: 10.7150/thno.100667. eCollection 2024.

Targeting sirtuins for cancer therapy: epigenetics modifications and beyond

Hui Shen  1 , Xinyi Qi  2   3 , Yue Hu  1 , Yi Wang  3   4 , Jin Zhang  3 , Zhongyu Liu  4 , Zheng Qin  1
Affiliations
Review

Targeting sirtuins for cancer therapy: epigenetics modifications and beyond

Hui Shen et al. Theranostics. .

Abstract

Sirtuins (SIRTs) are well-known as nicotinic adenine dinucleotide+(NAD+)-dependent histone deacetylases, which are important epigenetic enzymes consisting of seven family members (SIRT1-7). Of note, SIRT1 and SIRT2 are distributed in the nucleus and cytoplasm, while SIRT3, SIRT4 and SIRT5 are localized in the mitochondria. SIRT6 and SIRT7 are distributed in the nucleus. SIRTs catalyze the deacetylation of various substrate proteins, thereby modulating numerous biological processes, including transcription, DNA repair and genome stability, metabolism, and signal transduction. Notably, accumulating evidence has recently underscored the multi-faceted roles of SIRTs in both the suppression and progression of various types of human cancers. Crucially, SIRTs have been emerging as promising therapeutic targets for cancer therapy. Thus, in this review, we not only present an overview of the molecular structure and function of SIRTs, but elucidate their intricate associations with oncogenesis. Additionally, we discuss the current landscape of small-molecule activators and inhibitors targeting SIRTs in the contexts of cancer and further elaborate their combination therapies, especially highlighting their prospective utility for future cancer drug development.

Keywords: Cancer therapy; Epigenetics modification; Sirtuin (SIRT); Small-molecule activator; Small-molecule inhibitor.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The classification and subcellular localization of SIRTs. (A) SIRTs are classified as the Class III HDAC. (B) SIRTs have seven members (SIRT1-7) and have different subcellular localization.
Figure 2
Figure 2
The classification and structure of SIRTs. (A) Domain organization of SIRTs. (B-H) The three-dimensional structure of SIRTs and basic function. (SIRT1 PDB: 4I5I; SIRT2: 3ZGV; SIRT3: 4BV3; SIRT4: 5OJ7; SIRT5: 3RIG; SIRT6: 3ZG6; SIRT7: 5IQZ).
Figure 3
Figure 3
The regulation of SIRTs in cancer. The transcriptional regulation, post-transcriptional regulation, RNA-mediated regulation, protein regulation and other regulation of SIRT1-7.
Figure 4
Figure 4
The tumor suppressor role of SIRT1-7. SIRT1-7 can regulate different tumor processes by regulating different substrates, affecting tumor genomic stability, proliferation, metastasis, metabolism, response to tumor therapy and others.
Figure 5
Figure 5
The oncogenic role of SIRT1-7. The SIRT1-7 enzymes can facilitate tumor progression by modulating various substrates involved in tumor initiation, development, cell cycle regulation, epithelial-mesenchymal transition (EMT), apoptosis, autophagy, metabolism, genomic stability maintenance, and response to cancer therapeutics.
Figure 6
Figure 6
Mechanism of action of representative small molecule modulators targeting SIRTs.
Figure 7
Figure 7
The conceptualization and prospective avenues for targeting SIRTs in cancer therapy.
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