Mitochondrial sirtuins in cancer

Keywords

Mitochondria; Mitochondrial sirtuins; Cancer; Tumour suppressor; Tumour promoter

Description

The sirtuin family consists of seven members: SIRT1-7 which require nicotinamide adenine dinucleotide (NAD+) for their activity [1]. They localize into different compartments performing diverse functional roles. SIRT1, 6 and 7 localize in the nucleus, Sirt2 in the cytoplasm and SIRT3, 4,
and 5 mostly in mitochondria. Intriguingly, both functionally and structurally all members are highly conserved [2]. Sirtuins belong to the class III family of histone deacetylase (HDAC) and can control the transcription of various genes [3]. In addition, they also perform various other post translational
modifications (PTMs) using different acyl groups such as desuccinylation, demalonylation, decrotonylation, etc. to specific proteins and protein residues resulting in metabolic and biochemical regulation [4]. The three mitochondrial members of the sirtuin family (SIRT3, SIRT4 and SIRT5) in addition to those above-mentioned processes perform an additional role in maintaining mitochondrial fitness, dynamics and metabolic regulation. Moreover, mitochondrial cell signaling is extremely important in the context of cancer as cancer cells require constant energy through mitochondria or glycolysis in order to grow and proliferate. Several studies suggested that mitochondrial sirtuins can act
both as tumor promotors and suppressors in several cancers. Some of them are discussed below:

The role of SIRT3 in cancer

SIRT3 is involved in various cancer entities, however, its role is controversial. In breast cancer, SIRT3
expression levels are much lower than in normal tissue thereby activating the SRC/FAK signaling which enhances cancer progression through metastasis [5]. In contrast, SIRT3 overexpression decreases Reactive
Oxygen Species (ROS) and can influence the metabolic shift from glycolysis to oxidative phosphorylation (Oxphos) during aerobic respiration and thus acts as a tumor suppressor [6]. Furthermore, SIRT3 can activate mitochondrial ATP synthase subunit ATP5O and enhance ATP production resulting in enhanced Oxphos [7]. In neuroblastoma, SIRT3 is highly expressed and decrease of its levels increases mitochondrial membrane potential collapse through increase of ROS, suggesting SIRT3 to be a tumor promotor [8]. In lung and liver cancer, SIRT3 expression is downregulated and its exogenous overexpression suppressed the proliferation of liver cancer cells by activating the p53 pathway [9,10], In case of ovarian cancer, SIRT3 levels are also low and overexpression of SIRT3 reduces ovarian cancer cell proliferation [11], A similar mechanism has been reported
in pancreatic cancer where decreased levels of SIRT3 activate the malate-aspartate complex leading to higher production of ATP and thereby fueling the growth of cancer cells [12], In gastric cancer the role of SIRT3 is
contradictory as both elevated and decreased levels of SIRT3 were reported [13,14]. In colorectal cancer, higher SIRT3 levels deacetylate the serine hydroxymethyltransferase 2 (SHMT2), thereby enhancing serine consumption and cancer progression [15]. In prostate cancer, SIRT3 performs as a tumor suppressor as its low expression facilitates the acetylation of mitochondrial acotinase 2 (ACO2) which activates lipogenesis and promotes prostate cancer growth [16]. In contrast to the above-described cancer species, in thyroid cancer and esophageal cancer, SIRT3 levels are higher than in normal tissue. In the former, SIRT3 activates the catenin pathway and in the latter SIRT3 decreases the levels of p21 and BAX [17,18], Thus, in majority of the cancers SIRT3 acts a tumor suppressor by influencing different mitochondrial and cellular processes and pathways while in some it can also act as a tumour promoter. However, there are still detailed studies required in order to identify the downstream targets.

The role of SIRT4 in cancer

Lower SIRT4 levels increase glycolysis activity supporting cancer cell proliferation and survival in various types of cancer cells including breast cancer cells [19], neuroblastoma [20] pancreatic [21] and liver cancer [22]. In contrast, increasing SIRT4 expression halted the growth of neuroblastoma cells through decreased ATP production [23] characterizing SIRT4 as a tumor suppressor. On the other hand, in lung cancer, SIRT4 levels are much higher than in normal cells. Jeong et al. demonstrated that Sirt4 knockout mice develop lung cancer randomly through increased glutamine signaling [24] while in gastric cancer SIRT4 acted as tumor suppressor. SIRT4 levels were significantly lower and overexpression of SIRT4 arrested the cell cycle checkpoint G1 in gastric cancer [21]. In both colorectal and prostate cancer, SIRT4 expression levels were lower than in normal tissue. Over-expression of SIRT4 inhibited glutamine metabolism in the former while in the latter it inhibited the expression of the mitochondrial inner membrane protein ANT2 [25] A similar mechanism was observed in thyroid cancer as well as in leukemia where overexpression of SIRT4 inhibited glutamate dehydrogenase (GDH) and obstructed glutamine signaling leading to decreased proliferation of cancer cells [22]. Thus, SIRT4 can also act as tumor suppressor and thereby hinder cancer cell proliferation.

The role of SIRT5 in cancer

Contrasting to SIRT3 and SIRT4, SIRT5 levels are increased in breast cancer and neuroblastoma. They protect cells by decreasing apoptosis and ROS levels. In liver cancer, a study showed that SIRT5 acted as tumor suppressor as it was downregulated and as a result ACOX1 was succinylated and activated fueling cancer cells while another study demonstrated that SIRT5 was upregulated which then activated E2F1, a cell cycle control check point protein [26]. Higher SIRT5 levels were also observed in ovarian cancer which reduced ROS levels and promoted tumor progression. Similarly, in lung cancer higher SIRT5 levels activated NRF2 and SOD1 leading to rapid tumor progression while the reverse mechanism was found in gastric cancer where lower SIRT5 levels activated cyclin dependent kinase (CDK2) supporting cancer progression. Higher SIRT5 expression was also observed in colorectal and prostate cancer. SIRT5 demalonylated lactate dehydrogenase B (LDHB) and deglutarylated glutamate dehydrogenase 1 (GLUD1) [23] activating those enzymes resulting in a higher accumulation of lactate and glutamate which facilitated colorectal cancer growth. In prostate cancer SIRT5 stimulated cyclin D1 and hijacked cell cycle processes and thereby promoted the proliferation of prostate cancer cells [27]. In renal cell carcinoma a higher level of SIRT5 was found which desuccinylated succinate dehydrogenase (SDHA), a nuclearly encoded component of respiration complex II, supporting cancer development [28]. Taken together, SIRT5 acts as a tumor promotor in most of the analysed cancer types.

Conclusion

Mitochondrial sirtuins (mtSirts) play a critical role in the mitochondrial and metabolic regulation of cellular homeostasis. mtSirts interact with various substrates that are responsible for cancer progression and thus a better understanding of the function and mechanisms of action of mtSirts can provide a deeper insight of their importance in cancer biology. Further research should explore both upstream and downstream targets of mtSirts which would better characterize their dual nature of being both “tumor activator” as well as “tumor promotor”. Furthermore, via these new insights mitochondrial sirtuins could pose novel molecular targets for cancer management.