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Gene & Protein in Disease Human sirtuins (SIRT1-7) in cancer

genome stability, cell cycle regulation, apoptosis, and leukemia. SIRT2 dysregulation has been proven in both
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inflammation. The specific effects depend on the type patient tissues and peripheral blood and cancer cell lines.
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of sirtuin involved and the cellular context in which the Experiments on transgenic mice with SIRT2 deletion have
dysregulation occurs. Recent research has shown that shown the development of smaller, less proliferative, and
sirtuins play a dual role in cancer, exhibiting either oncogenic more differentiated hepatocellular tumors, suggesting the
or tumor-suppressive characteristics depending on the tumor-promoting characteristic of SIRT2. SIRT2 can act
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tumor type, genetic makeup, and microenvironment. 44-46 as an oncogene and a tumor suppressor. SIRT2 promotes
cell proliferation and tumor growth by further enhancing
3.1. SIRT1 the expression of certain oncogenes (e.g., Slug – snail
SIRT1 plays conflicting roles in tumorigenesis, depending family transcriptional repressor 2, avian myelocytomatosis
on its localization and cell type. It has an oncogenic effect viral-related oncogene, and aldehyde dehydrogenase 1
as an inhibitor of p53 and other tumor suppressors and can family member A1) and inhibiting the expression of
act as a tumor suppressor, negatively regulating β-catenin tumor suppressors (e.g., arrestin domain containing 3).
and survivin. SIRT1 dysregulation has been proven in It promotes the proliferation, migration, and invasiveness
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various cancer cell lines, such as prostate cancer and of tumor cells through the protein kinase B/glycogen
melanoma; in tumor tissue samples from patients with synthase kinase 3/β-catenin signaling pathway and the
breast cancer, colorectal cancer, or hepatocellular inhibition of p21 through nuclear factor-kappa B (NF-κB)/
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cancer; and in the peripheral blood of patients with acute Snail. However, SIRT2 may also inhibit tumor growth by
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myeloid leukemia. 51 deacetylating and inactivating the transcription factor
NF-κB, which is involved in the inflammatory response
p53 functions as a tumor suppressor and is linked to and cancer progression. SIRT2 can prevent further tumor
oxidative stress and DNA damage. Its activation induces growth by suppressing certain oncogenes (e.g., Jumonji C
cell cycle arrest and, if the damage is irreparable, triggers domain 2A and ATP citrate lyase). SIRT2 overexpression
apoptosis. SIRT1 overexpression notably reduces p53- promotes Skp2 deacetylation and degradation, resulting in
mediated apoptosis caused by DNA damage and oxidative increased p27 and suppression of tumor cell growth. SIRT2
stress by directly deacetylating lysine 382 of p53. also preserves genome stability by interacting with ATR
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In addition, through β-catenin deacetylation, SIRT1 Interacting Protein and the anaphase promoting complex/
suppresses tumorigenesis and significantly hinders the cyclosome, reduces the antioxidant function of Prdx-1,
formation and proliferation of colorectal cancer cells. and prevents vascularization by inhibiting HIF-1α.
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In breast cancer gene 1 (BRCA1) mutation–associated SIRT2 can affect tumor growth through its interaction
breast cancer cells, SIRT1 inhibits survivin, an apoptosis- with the surrounding tumor microenvironment and either
suppressing protein that promotes proliferation and is often promotes (changing the microenvironment pH, improving
overexpressed in various cancers. Breast cancer cells with cell energy metabolism, and promoting immune
BRCA1 mutations exhibit low SIRT1 expression and high avoidance) or inhibits (inhibiting tumor angiogenesis and
levels of survivin. BRCA1 binds to the SIRT1 promoter, fibroblast activity) cancer cell growth. 65
elevating SIRT1 expression and consequently inhibiting
survivin by modifying histone H3’s epigenetic state. The 3.3. SIRT3
absence of SIRT1 impedes survivin regulation by BRCA1. 54
Elevated SIRT3 expression in tumor tissue is linked to
Studies showing SIRT1’s involvement in cancer poor clinical prognosis in patients with cancer. SIRT3
have been published for the past two decades. Early dysregulation plays a role in the development and progression
experiments on mice with overall overexpression of of various cancer cell lines, including gastric cancer,
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SIRT1 have demonstrated the dual character of SIRT1 in colorectal cancer, breast cancer, and melanoma, and
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cancer, exhibiting both protective and promoting effects. in patient tumor tissue, including esophageal and renal
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Transgenic mice with overall SIRT1 overexpression cancers. Physiologically, SIRT3 acts as a mitochondrial
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showed lower susceptibility to aging-associated and tumor-suppressive protein, and impaired and aberrant
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metabolic syndrome-associated cancers. However, in mitochondrial function can lead to cancer development.
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studies with human cancer cell lines and patient tissues, Disruption in SIRT3 expression and function can result
SIRT1 overexpression promoted metastatic potential. 57,58 in oxidative damage, ROS accumulation, and abnormal
ROS-driven signaling, leading to metabolic changes in the
3.2. SIRT2
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mitochondria. SIRT3 suppresses tumor growth driven by
SIRT2 is dysregulated in multiple tumor types, gastric glycolysis. In low-oxygen environments, increased SIRT3
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cancer, ovarian cancer, melanoma, and acute myeloid levels reduce ROS production, inhibit glycolysis, limit cell
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Volume 3 Issue 4 (2024) 5 doi: 10.36922/gpd.4100