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

proliferation, and prevent HIF-1α stabilization and activity, enzyme for fatty acid oxidation. CPT1A inhibition reduces
ultimately decreasing tumor formation. 73 the breakdown of fatty acids used for energy production,
SIRT3 may affect tumor growth in several ways. impacting cancer cells that depend on fatty acid oxidation
PDHA1 deacetylation promotes the transformation of to meet their energy demands, especially under nutrient-
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pyruvate to acetyl coenzyme A, thereby favoring oxidative deprived conditions. As a mitochondrial sirtuin, SIRT4
phosphorylation over glycolysis. This can inhibit the affects ROS levels and the DNA damage response. SIRT4
rapid proliferation of cancer cells that rely on glycolysis. influences the expression and activity of SOD2 or genes
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Deacetylation and activation of isocitrate dehydrogenase involved in DNA repair mechanisms, such as BRCA1 and
2 and SOD2 may reduce ROS levels and generally reduce radiation sensitive 51 recombinase, helping to maintain
oxidative stress and DNA damage, thereby preventing low levels of ROS and thereby reducing oxidative DNA
genomic instability that can lead to cancer progression. 75,76 damage and genomic instability, which contribute to
cancer progression. 87
SIRT3 deacetylates and stabilizes p53, which can
suppress tumor cell growth through cell cycle arrest and 3.5. SIRT5
apoptosis. SIRT3 also deacetylates Ku70, a constituent of SIRT5 can act as an oncogene or as a tumor suppressor.
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the NHEJ pathway involved in DNA repair. By promoting It promotes cancer cell survival, proliferation, metastasis,
accurate DNA repair, SIRT3 helps maintain genomic and chemotherapy resistance. The oncogenic activity of
integrity and prevent mutations that could lead to cancer. SIRT5 has been observed in mice with SIRT5 deletion that
SIRT3 can promote apoptosis through the activity of BAX, develop colorectal and breast cancer tumors. SIRT5
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a proapoptotic protein. By promoting apoptosis, SIRT3 dysregulation related to tumor proliferation has been also
helps eliminate damaged or cancerous cells. 78 reported in cancer cell lines and tumor tissue samples from
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3.4. SIRT4 patients with breast cancer and ovarian cancer and in
mononuclear and CD34+ cells of patients with acute
Low SIRT4 expression has been reported in patient tumor myeloid leukemia. 91
tissues and cell lines of thyroid, lung, bladder, and
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ovarian cancers. SIRT4 downregulation is associated As a tumor suppressor, SIRT5 interacts with various
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with poor patient prognosis, as it is frequently observed proteins and post-translationally modifies them to hinder
in advanced-stage and metastatic tumors, and SIRT4 cell proliferation, disrupt the immune response, and inhibit
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overexpression in tumor tissue may have tumor- angiogenesis and metastasis. Studies have reported the
association of low SIRT5 expression with poor prognosis in
suppressive effects. SIRT4 exerts an antiproliferative 93 94
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effect on damaged and cancer cells through its inhibitory tissues of patients with glioblastoma and thyroid cancer.
effect on glutamine metabolism. Because SIRT4 exerts 3.6. SIRT6
inhibitory effects on the proliferation of cells with
damaged DNA, its expression physiologically increases Due to its role in maintaining genome stability and
during DNA damage. In many tumors, the protective telomere integrity, SIRT6 dysregulation appears to be an
effect of SIRT4 decreases due to downregulation of its important step in molecular carcinogenesis. It interacts
expression, which can result in a tumorigenic phenotype with and deacetylates telomeric repeat–binding factor
by enhancing the proliferation of glutamine-dependent 2 (TRF2), a protein involved in the protection and
cells. SIRT4 inhibits glutaminase, the enzyme responsible maintenance of telomeres, which are sequences at the
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for converting glutamine into glutamate. Glutamine, the ends of chromosomes characterized by repetitive DNA.
most abundant, free non-essential alpha-amino acid in By regulating TRF2 activity, SIRT6 influences telomere
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the cell cytosol and human blood, is essential for protein integrity and stability. SIRT6 also interacts with and
synthesis. Many tumor cells rely on glutamine for rapid deacetylates poly(ADP-ribose) polymerase 1 (PARP1),
growth, and certain types of cancer cells cannot survive an enzyme involved in BER and DNA single-strand break
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without an external glutamine supply. SIRT4 suppresses repair, and Ku70 and Ku80, which are involved in DNA
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glutamine metabolism in the mitochondria of tumor DSBR. By regulating PARP1 activity and efficient
cells through ADP-ribosylating GLUD, which decreases DSBR, SIRT6 promotes DNA repair and genomic stability
energy and glutamine availability in proliferating tumor and helps prevent chromosomal aberrations and genomic
cells. This inhibition allows time for damaged DNA to instability associated with cancer.
be repaired and helps maintain genome stability. SIRT4 Depending on the biological context, SIRT6 acts as
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can also affect cell metabolism by inhibiting carnitine either a promoter or a tumor suppressor in tumorigenesis.
palmitoyltransferase 1A (CPT1A), which is an essential The tumor-suppressive function of SIRT6 has been proven

Volume 3 Issue 4 (2024) 6 doi: 10.36922/gpd.4100