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Review
. 2021 Oct;22(4):731.
doi: 10.3892/ol.2021.12992. Epub 2021 Aug 11.

Emerging role of SIRT2 in non-small cell lung cancer

Mengge Zheng  1 , Changyong Hu  1 , Meng Wu  1 , Yue Eugene Chin  1
Affiliations
Review

Emerging role of SIRT2 in non-small cell lung cancer

Mengge Zheng et al. Oncol Lett. 2021 Oct.

Abstract

Non-small cell lung cancer (NSCLC) is one of the most devastating cancer types, accounting for >80% of lung cancer cases. The median relative survival time of patients with NSCLC is <1 year. Lysine acetylation is a major post-translational modification that is required for various biological processes, and abnormal protein acetylation is associated with various diseases, including NSCLC. Protein deacetylases are currently considered cancer permissive partly due to malignant cells being sensitive to deacetylase inhibition. Sirtuin 2 (SIRT2), a primarily cytosolic nicotinamide adenine dinucleotide-dependent class III protein deacetylase, has been shown to catalyze the removal of acetyl groups from a wide range of proteins, including tubulin, ribonucleotide reductase regulatory subunit M2 and glucose-6-phosphate dehydrogenase. In addition, SIRT2 is also known to possess lysine fatty deacylation activity. Physiologically, SIRT2 serves as a regulator of the cell cycle and of cellular metabolism. It has been shown to play important roles in proliferation, migration and invasion during carcinogenesis. It is notable that both oncogenic and tumor suppressive functions of SIRT2 have been described in NSCLC and other cancer types, suggesting a context-specific role of SIRT2 in cancer progression. In addition, inhibition of SIRT2 exhibits a broad anticancer effect, indicating its potential as a therapeutic for NSCLC tumors with high expression of SIRT2. However, due to the diverse molecular and genetic characteristics of NSCLC, the context-specific function of SIRT2 remains to be determined. The current review investigated the functions of SIRT2 during NSCLC progression with regard to its regulation of metabolism, stem cell-like features and autophagy.

Keywords: NSCLC; function; pathogenic mechanism; sirtuin 2; therapeutic target.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Detailed schematic diagram of each domain of the SIRTs family. SIRTs 1–7 have numerous types of isoforms, but only the longest isoforms are shown in this figure. SIRT, sirtuin.
Figure 2.
Figure 2.
Schematic diagram of the mechanism of action of SIRT2 in NSCLC. RalB lysine fatty acylation promotes membrane localization and A549 cell migration. SIRT2 can significantly inhibit the formation and plasma membrane localization of the RalB-Sec5-Exo84 exocyst complex by regulating RalB8K lysine fatty acylation. Therefore, SIRT2 suppresses migration of A549 lung cancer cells by downregulating RalB8K lysine fatty acylation. SPOP can bind to SIRT2 and mediate its degradation by the proteasome. Subsequently, it inhibits the growth of NSCLC. By deacetylating the RRM2 K95 subunit of RNR, SIRT2 contributes to dNTP synthesis and DNA replication, thereby promoting the growth of lung cancer cells. The E3 ubiquitin ligase HRD1 binds to SIRT2 and promotes its degradation, which hinders the anticancer effect of SIRT2. By deacetylating AKR1C1, SIRT2 attenuates AKR1C1-STAT3 binding and STAT3 phosphorylation, thereby inhibiting the transcriptional activity of STAT3 target genes. SIRT2, sirtuin 2; NSCLC, non-small cell lung cancer; RalB, Ras-like proto-oncogene B; SPOP, speckle type BTB/POZ protein; RRM2, ribonucleotide reductase regulatory subunit M2; RNR, ribonucleotide reductase; HRD1, E3-ubiquitin protein ligase HRD1; AKR1C1, aldo-keto reductase family 1 member C1.
Figure 3.
Figure 3.
A schematic diagram of the biological functions of SIRT2. SIRT2, sirtuin 2.
See this image and copyright information in PMC

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Grants and funding

The present study was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, as well as by a grant from the China Natural Science Foundation (grant no. 31801058).