SIRT2 as a Therapeutic Target in Cancer: Recent Advances and Challenges

What is SIRT2？

SIRT2 is a predominantly cytoplasmic protein that deacetylates a number of cytoplasmic substrates, including-tubulin involved microtubule dynamics. However, SIRT2 has also been observed in the nucleus, where it has been implicated in deacetylation of histones and several transcription factors, including p53 and FOXO proteins. SIRT2 has a key role in cell cycle progression.

The Structure of SIRT2

The SIRT2 gene in humans is located on chromosome 19, spanning a total of 21 kilobases across 16 exons within the genomic DNA. Interestingly, the SIRT2 transcript undergoes alternative splicing, resulting in the production of three distinct isoforms. These isoforms exhibit variations in cellular distribution and function[1].

Isoform 1 is the full-length variant and is predominantly found in skeletal muscle tissue. On the other hand, isoform 2 lacks the initial 37 residues and is primarily concentrated in the brain. Remarkably, both isoform 1 and isoform 2 display enzymatic activity and possess the ability to move between the nucleus and cytoplasm. In contrast, isoform 5 lacks a nuclear export signal (NES), which leads to its accumulation within the nucleus, accompanied by a loss of catalytic activity[2].

Studies utilizing X-ray crystallography have unveiled crucial insights into the structural components of human SIRT family enzymes. These enzymes are characterized by two primary functional domains: a smaller domain that interacts with zinc ions and a larger domain responsible for binding to NAD+[3]. Additionally, a conserved substrate binding groove is located at the interface of these two domains. The longest isoform of SIRT2 consists of 389 amino acids, with the catalytic domain relying on NAD+ spanning from amino acids 65 to 340. Notably, the N-terminal segment of SIRT2, encompassing amino acids 41 to 51, serves as the nuclear export signal (NES) responsible for directing the protein's localization to the cytoplasm[4].

Functions of SIRT2

SIRT2 biological functions

Mammalian SIRT2 showcases a multifaceted range of biological functions. One of its notable roles is in cell cycle regulation through its deacetylase activity. During mitosis, SIRT2 associates with chromatin and aids in condensing it by deacetylating Histone H4 lysine (H4K) 16. This deacetylation is crucial for the proper deposition of H4K20 methylation during mitosis. The cell cycle regulatory function of SIRT2 is underscored by increased levels of mitotic regulators observed in SIRT2-knockout mice[6].

SIRT2's influence extends to mitosis regulation by deacetylating two adenomatous polyposis coli/C coactivators, cadherin-1, and cell division cycle protein 20 homolog[6]. Beyond mitosis, SIRT2 also plays a role in the S phase of the cell cycle. It deacetylates the K95 site of ribonucleotide reductase regulatory subunit M2, which amplifies the dNTP pool size and accelerates DNA replication fork progression. This acceleration leads to heightened cancer cell proliferation rates[7].

Moreover, SIRT2 impacts cell metabolism, particularly in cancer. It promotes the metastasis of gastric cancer via the RAS/ERK/JNK/matrix metalloproteinase-9 pathway by boosting phosphoenolpyruvate carboxykinase 1-associated metabolism. SIRT2 enhances glycolysis and tumor growth by deacetylating pyruvate kinase M2 at the K305 site, a pivotal enzyme bridging metabolism and immunity[8]. Understanding SIRT2's role and mechanisms in various cancer types is crucial, as reflected in Table I, which provides clinical data and mechanisms of action for SIRT2 in cancer.

SIRT2's metabolic influence extends to glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. SIRT2 deacetylates G6PD at residue K403, increasing its activity and NADPH production[9]. It's worth noting that SIRT2 can inhibit glycolysis and metabolic reprogramming in induced pluripotent stem cells (iPSCs) by deacetylating four key glycolytic enzymes: Aldolase, phosphoglycerate kinase 1, enolase, and GAPDH.

Additionally, SIRT2 assumes the role of a master organizer in T-cell metabolism, inhibiting glycolysis and impairing T-cell effector functions by deacetylating various metabolic enzymes[9].

Apart from its classical deacetylase activity, SIRT2 demonstrates the ability to remove long chain fatty acyls from Kras4a and Ras-like proto-oncogene B (RalB)[10]. Furthermore, SIRT2's de-myristoylation activity has been identified in ADP-ribosylation factor 6 lysine 3. The extensive functions of SIRT2 span the nervous system, mitosis, genome integrity, cell differentiation, cell homeostasis, aging, infection, inflammation, oxidative stress, and autophagy[11].

SIRT2 function in various tumor types

The role of SIRT2 in cancer is a complex tale, where dysregulation due to gene amplification, mutation, overexpression, or mislocalization has been associated with the progression of various cancer types. In a cross-cancer analysis of The Cancer Genome Atlas database, it's revealed that the SIRT2 gene is amplified in approximately 9% of ovarian epithelial tumors (52 out of 584 cases) and 4% of non-small cell lung cancers (41 out of 1,053 cases). Conversely, the gene locus of SIRT2 is frequently deleted in human oligodendrogliomas, and somatic mutations within SIRT2 are found in endometrial carcinoma, melanoma, leukemia, and NSCLC. Remarkably, several of these mutations, occurring at evolutionarily conserved sites, have been identified as functionally significant[12].

However, due to the intricate nature of tumors, the expression pattern of SIRT2 can be quite variable. Recent review articles have highlighted elevated SIRT2 expression in neuroblastoma, uveal melanoma, renal cell carcinoma, and acute myeloid leukemia. Conversely, reduced expression has been observed in glioma, neck squamous cell carcinoma, breast cancer, prostate cancer, and liver cancer[13]. Intriguingly, NSCLC presents a dual SIRT2 expression pattern, where mRNA and protein levels are downregulated, but the protein expression is significantly higher in lung primary tumors compared to normal tissues. Notably, low SIRT2 expression in NSCLC has been linked to longer overall survival, and its expression is associated with survival time in lung adenocarcinoma[14].

Despite its ability to shuttle between the nucleus and cytoplasm, SIRT2 predominantly resides in the cytoplasm. Interestingly, high levels of mislocalized nuclear SIRT2 protein correlate with shorter disease-free survival in ER-negative breast cancer. Moreover, a combination of SIRT1 and SIRT2 has proven to be a more effective recurrence-free survival prediction model for NSCLC. SIRT2 has also emerged as a potential plasma biomarker in invasive cervical cancer[15].

The role of SIRT2 in cancer remains contentious. Initially viewed as a tumor suppressor due to its regulatory influence on the mitotic checkpoint and deacetylase activity on histone H3K56, a common modification in cancer cells, SIRT2's tumor-suppressive function was supported by genetic experiments showing increased tumor incidence in Sirt2-deficient mice. However, contrasting evidence suggests its tumor-promoting activity through the deacetylation of p53, leading to a reduction in its transcriptional activity. Additionally, SIRT2's deacetylation of K5 on lactate dehydrogenase A boosts glycolysis, lactate production, and consequently, cancer cell proliferation and migration[17].

Furthermore, the therapeutic potential of SIRT2 inhibitors in cancer treatment has been recognized, highlighting their broad anticancer activity[18]. This duality in function underscores the complexity of SIRT2's involvement in cancer.

Expression of SIRT2 in Tumors.

SIRT2, a member of the sirtuin family, is widely distributed in the human body, with prominent expression in various organs, including the brain, ovary, esophagus, heart, lung, testis, thyroid, spleen, and liver. Among these, the brain exhibits the highest expression level of SIRT2.

However, the expression of SIRT2 varies significantly among different types of tumors. In conditions such as human neuroblastoma, uveal melanoma, renal cell carcinoma, and acute myeloid leukemia, SIRT2 levels are notably elevated compared to normal tissues. Intriguingly, recent snRNA-seq studies have unveiled that SIRT2 expression can be remarkably high in specific groups of cells within cancer tissues, despite its generally lower expression levels.

Studies focusing on renal cancer have revealed a correlation between high SIRT2 expression and adverse patient outcomes. Specifically, patients with elevated SIRT2 levels tend to have a poorer prognosis than those with lower SIRT2 expression. Additionally, SIRT2 plays a role in promoting the formation of tumor cell clusters, enhancing their resistance to fluorescence-induced apoptosis. Furthermore, following kidney transplantation, patients with high SIRT2 expression levels have a lower likelihood of tumor recurrence compared to those with lower SIRT2 expression levels.

SIRT2 Regulates Tumor Microenvironment

SIRT2 not only directly influences the cell cycle of cancer cells but also plays a crucial role in shaping the tumor microenvironment, impacting tumor cell invasion and metastasis.

SIRT2's involvement in the tumor microenvironment includes mediating immune evasion, enhancing cell energy metabolism, and altering the alkaline environment. Tumors often rely on immune evasion mechanisms to thrive, and SIRT2 contributes to this process by maintaining T-cell homeostasis and inducing Treg cells, thereby limiting the tumor immune response. Additionally, within cancer tissues, SIRT2 suppresses tumor-associated macrophages, myeloid-derived cells, and tumor-associated neutrophils, weakening the immune response and aiding tumor cells in escaping immune surveillance. Furthermore, SIRT2 can boost mitochondrial metabolism and inhibit the E-cadherin pathway, promoting the invasion of liver cancer cells. Notably, SIRT2 can also modify the alkaline environment, deacetylating lactic dehydrogenase (LDH), increasing its enzyme activity, leading to the accumulation of lactic acid, and ultimately promoting tumor cell proliferation.

Conversely, SIRT2 can hinder tumor cell growth by interacting with the tumor microenvironment. It inhibits fibroblast activity and interferes with tumor angiogenesis. Tumor angiogenesis is pivotal for delivering oxygen and nutrients to cancer cells. SIRT2 is known to inhibit the production of vascular endothelial growth factor and connective tissue growth factor by tumor cells or fibroblasts within the matrix, effectively impeding tumor cell development. Furthermore, SIRT2 targets ATP-citrate lyase (ACLY), a key player in cell membrane extension and cell proliferation. In numerous types of tumor cells, SIRT2 deacetylates ACLY, reducing its stability and thereby inhibiting tumor cell proliferation.

In summary, SIRT2's impact on the tumor microenvironment varies depending on the specific metabolic requirements of different cells. It interacts with the tumor microenvironment through various mechanisms, including mediating immune evasion, modulating energy metabolism, altering cellular acidity, inhibiting fibroblast activity, and impeding angiogenesis.

SIRT2 Protein

Recombinant Human SIRT2 Protein

Cilck here for more SIRT2

Synonym : SIR2L, SIR2L2, Sirtuin 2

References:

 

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