Decreased SIRT1 expression

Biological state: 

Mammalian SIRTs include seven proteins (SIRT1-7) with deacetylase activity belonging to the class III histone deacetylase family. SIRTs share homology with the yeast deacetylase Sir2, and have different sequences and lengths in both their N- and C-terminal domains (Carafa, V. et al 2012). Expressed from bacteria to humans (Vaquero, A. 2009), SIRTs target histone and non-histone proteins.

Localization of SIRTs is restricted to mitochondria, cytoplasm and nucleus     The location of SIRT1, SIRT6, and SIRT7  is predominantly in the nucleus,  while SIRT2 in the cytosol, and SIRT3, SIRT4, and SIRT5 are in the mitochondria.  Depending on their role in regulating different pathways,  SIRTs relocalize under different conditions such as  cell cycle phase, tissue type, developmental stage, stress condition, and metabolic status which has been documented in the literature. (McGuinness, D. et al 2011).  As per Mitchishita et al, SIRT1, SIRT2, and SIRT7 are often found in both the nucleus and cytoplasm (Michishita, E et al 2005).

 Cellular pathways  like DNA repair, transcriptional regulation, metabolism, aging, and senescence are modulated by Sirtuins. This has  created  sufficient interest with Sirtuins as target in cancer research as the above mentioned functions are involved in initiation and progression of cancer. Evidence have suggested the association of SIRTs with metabolism-associated TFs, MYC and hypoxia inducible factor-1 (HIF-1),  in terms of  energy metabolic reprogramming.( Zwaans, B. M. et al 2014)

  The biological effect of SIRTs in cancer is either tumor suppression  or tumor promoter (oncogenes) action by altering the cell proliferation, differentiation, and death which in turn depends on cell context and experimental conditions.   These two totally opposite function of SIRTs on cancer cell is remains a highly debated and controversial topic. Whether SIRTs act as tumor suppressors or promoters depends on (i) their  The different expression levels of SIRTS in tumors and its effects on cell cycle, cell growth,  death, their action on specific proto-oncogene and onco-suppressor proteins will determine SIRTs role as  tumor suppressor or tumor promoters  (Deng, C. X. 2009).

Sirtuin Reactions

The NAD+-dependent deacetylation is well known enzymatic reaction catalyzed by SIRTs. Deacetylation reaction begins with amide cleavage from NAD+ with the formation of nicotinamide and an intermediate of reaction, O-ADP-ribose. This intermediate formed is necessary for the deacetylation process by which SIRTs catalyze the transfer of one acetyl group from a lysine to O-ADP-ribose moiety to form O-acetyl-ADP-ribose and the deacetylated lysine product. This reaction requires a mole equivalent of NAD+ per acetyl group removed and is controlled by the cellular [NAD]/[NADH] ratio (Sauve, A. A. 2010 and Shi, Y. et al 2013).

Among the SIRTs family, only SIRT1, SIRT2, and SIRT3 possess a robust deacetylase activity even though SIRT enzymes are primarily known as protein deacetylases. SIRT4, SIRT5, SIRT6, and SIRT7) exhibit a weak or no detectable deacetylation activity at all.Through these reactions, SIRTs are able to regulate several key cellular processes (Jiang, H., et al 2013 and Zhang, S. et al 2017).

Biological compartments: 

Regulation of gene expression takes place in the cell, subcellular site being nucleus.

General role in biology: 

Silent Inflammation Regulator 2 (SIR2) proteins belong to the  family of histone deacetylases (HDACs) that catalyze deacetylation of both histone and non- histone lysine residues.

Mammalian sirtuins (SIRT1-7) are involved in  diverse biological processes including energy metabolism,  lifespan and health span regulation (Longo VD et al 2006). Mammalian sirtuins possess will bring about an array of biological functions through its enzymatic activity such as  histone deacetylase, mono-ADP-ribosyltransferase, desuccinylase, demalonylase, demyristoylase, and depalmitoylase activity (Michan S et al 2007). SIRT1 located  in the nucleus play an important role in genomic stability, telomere maintenance, and cell survival (Chen J et al 2011 and, Haigis MC et al 2006).

Among the 7 SIRTs, SIRT1 is the largest in terms of total DNA and amino acid sequence studied sirtuin [Fang, Y. and M.B. Nicholl 2011]. SIRT1, a class 3 histone deacetylase, is implicated in the modulation of apoptosis, senescence, proliferation, and aging. It’s actions arebrought about by cellular nicotinamide adenosine dinucleotide (NAD+) which acts as a cofactor for deacetylation reactivity. The liberated nicotinamide from NAD+, generates a  novel metabolite o-acetyl-ADP-ribose . SIRT1 can mediate  the actions at translational level. Various mechanisms have been  proposed to be  involved in dysregulation of SIRT1 in cancer cells  [Yao, C., et al.2016]. In human breast, lung and prostate cancers SIRT1 is significantly elevated . It plays  a role in tumorigenesis by anti-apoptotic activity through oncogene and epigenetic regulator action.[ Saunders, L. and E. Verdin 2007]. SIRT1 deacetylates pro-apoptotic proteins such as p53 and promotes cell survival under genotoxic and oxidative stresses [Kojima, K., et al 2010]. It’s critical role in multiple aspects of resistance to anti-cancer drugs is also well documented [Duan, K., et al 2015]. Therefore, SIRT1 overexpression is associated with the subsequent higher level of tumor cell proliferation, invasion, and migration [Wang, X., et al 2016].

SIRT1 expression is increased in human colon cancer, acute myeloid leukemia, and some skin can- cers (Bradbury, C. A et al 2005, Hida, Y. et al 2007, Huffman, D. M. et al 2007 and Stunkel, W.2007). SIRT1 , by interacting with and inhibiting p53  may act as tumor promoter (van Leeuwen, I., and Lain, S. 2009). Repression of tumor suppression protein expression and DNA repair protein ,are other roles of  SIRT1 in cancer cells.  In colon cancer ,  SIRT1 limits β-catenin signaling while in breast cancer it interacts with  BRCA1 signaling . However it has been observed that  SIRT1 expression is decreased in  ovarian cancer, glioblastoma, and bladder carcinoma (Deng, C. X. 2009).  In these cancers , SIRT1 might serve as a tumor suppressor by blocking oncogenic pathways. Thus SIRT1 can serve as a tumor promoter or tumor suppressor, depending on the oncogenic pathways specific to particular tumors.

In hepatocellular carcinoma , SIRT1 was overexpressed in HCC cells and tissues, and significantly promoted the migration and invasion ability of HCC cells by inducing the epithelial and mesenchymal transition[Hao C et al 2014]. This in vivo study  also supported the oncogenic functions of SIRT1 in enhancing metastasis[Hao C et al 2014]. Bae et al [Bae HJ et al 2014] found that knockdown of SIRT1 inhibited cell growth by transcriptional deregulation of cell cycle proteins, leading to hypophosphorylation of pRb, which inactivated E2F/ DP1 target gene transcription, and thereby caused the G1/S cell cycle arrest. In addition, miR29c was identified as a suppressor of SIRT1 by comprehensive miRNA profiling and ectopic miR29c expression recapitulated SIRT1 knockdown effects in HCC cells [Bae HJ et al 2014].  To contradict the above findings,  Zhang et al [Zhang ZY et al 2015] reported that SIRT1 has anticarcinogenic effects in HCC via the AMPK mammalian target of rapamycin (mTOR) pathway. They evaluated the relationship between p53 mutations and activation of SIRT1 in 252 patients with hepatitis B virus positive HCC and found that activated SIRT1 was associated with a longer recurrence free survival in HCC tissues harbouring mutant p53.  He reported that inhibition of SIRT1 increased cell growth, bearing mutated p53, by suppressing AMPK activity and enhancing mTOR activity.The conflicting results from different published data  indicated that SIRT1 is multifunctional gene and its biological features are left unsolved.

These above evidence indicates the involvement of SIRTs in regulating three important tumor processes: epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. Many SIRTs are responsible for cellular metabolic reprogramming and drug resistance by inactivating cell death pathways and promoting uncontrolled proliferation. These observations are  for the future development of novel tailored SIRT-based cancer therapies.

Wang et al showed that SIRT1 expression was increased in several cancer cell lines, and is generally associated with poor prognosis and overall survival (Wang, C., et al 2017). Vaziri et al reported that SIRT1 interacted  with P53, triggering its deacetylation in Lys382 residue, and determined a block of all P53-dependent pathways, leading to uncontrolled cell cycle and inactivation of the apoptotic process (Vaziri, H., et al 2011).

SIRT1 has a function in metastasis and invasiveness in several cancers that has been reported in several studies. Among them ,the deacetylation of many proteins involved in tumor suppressor processes or DNA damage repair, and the inactivation of specific pathways support the role of SIRT1 as a tumor promoter. The role of  SIRT1  in the initiation, promotion, and progression of several malignant tumors including prostate cancer (Jung-Hynes, B. et al 2009), breast cancer (Jin, X., et al 2018), lung cancer (Han, L. et al 2013) and gastric cancer (Han, L. et al 2013) are well documented. Wilking el al showed in his in vitro experiments that the inhibition of SIRT1 by treatment with small molecule SIRT1 inhibitors determines a significant decrease in cell growth, proliferation and viability (Wilking, M. J., et al 2014).

Decreased SIRT1 expression  is known to be highly conserved throughout evolution and is present from humans to invertebrates.