Function of Sirtuins in Cancer Stem Cells

C l i n M e d International Library Citation: Dong Z, Cui H (2016) Function of Sirtuins in Cancer Stem Cells. Int J Stem Cell Res Ther 3:024. doi.org/10.23937/2469-570X/1410024 Received: December 14, 2015: Accepted: February 05, 2016: Published: February 08, 2016 Copyright: © 2016 Dong Z, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Dong and Cui. Int J Stem Cell Res Ther 2016, 3:024

As the most important member in sirtuins, SIRT1 regulates multiple cellular processes including DNA repair, aging, metabolism, cell cycle, and survival [13] and plays an important role in maintaining self-renewal and differentiation of embryonic stem cells and hematopoietic stem cells (HSCs), especially under conditions of outside stress [14].SIRT1 is a controversial histone deacetylase in tumorigenesis as it deacetylates both oncogenes such as β-catenin, survivin, and nuclear factor-κB (NF-κB) and tumor suppressors such as p53 and fork-head class O (FOXO) transcription factor [15].But recently studies showed that SIRT1 was highly expressed in cancer stem cells, including glioma stem cells (GSCs) [16], colorectal cancer stem cells (CCSCs) [17], breast cancer stem cells (BCSCs) [18], pancreatic cancer stem cells (PCSCs) [19], chronic myeloid leukemia (CML) [20] and acute myeloid leukemia (AML) stem cells [21] and acted as an important promotors in the maintenance and self-renew properties of these CSCs.
High expression of SIRT1 was found in CD133-positive glioma cells, which played an important role in tumor recovery and radiotherapy resistance.Knockdown of SIRT1 expression in these cells enhanced radiosensitivity and radiation-induced apoptosis in vitro and the mean survival rate of radiotherapy-treated mice bearing glioblastoma-CD133-positive tumors was significantly improved by SIRT1 knockdown as well [22].Further study showed that SIRT1 increased expression in GSCs (CD133, sex determining region Y-box 2 (Sox2), and nestin positive) and cancerous neural stem cells (CNSCs) and played an important role in escaping p53-dependent  tumor surveillance, thus induced oncogenic transformation and retained the neural cancer stemness of the cells [16].In addition, SIRT1 expression was decreased in cells of glial type (glial fibrillary acidic protein (GFAP)-positive) after differentiation from GSCs [16].Besides, another study also showed that translation of SIRT1 in nestin and notch intracellular domain (NICD)-positive GSCs was suppressed by cytoplasmic polyadenylation element binding protein 1 (CPEB1), a key modulator that induced differentiation at the post-transcriptional level [23].These evidences indicated that SIRT1 played an essential role in GCSs and could be a therapeutic target of GSCs.SIRT1 is overexpressed in human leukemia stem cells (LSC) and its inhibition increased apoptosis in LSC and suppressed proliferation of CML stem cells or primitive progenitor cells.Besides, inhibition SIRT1 in CML stem cells facilitated to eliminate CSCs by Imatinib, a breakpoint cluster region-c-Abl oncogene 1 (BCR-ABL) tyrosine kinase inhibitor (TKI), in part via p53 activation [20].In SIRT1 homozygous knockout BALB/c mice models, CD150-negtive side population (SP) CML stem cells was also reduced and the maintenance of these cells was compromised.It seemed that SIRT1 knockout reduced cyclin-dependent kinase 6 (CDK6) expression and activated p53 through deacetylation instead of increasing its expression [24].Except for CML stem cells, in primary human fms-like tyrosine kinase 3 internal tandem duplicated (FLT3-ITD) AML stem cells, SIRT1 was also selectively expressed in a high level and was enhanced by proto-oncogene c-MYC-induced high expression of ubiquitin specific peptidase 22 (USP22), a deubiquitinase (Figure 2).Besides, SIRT1 inhibition combined with FLT3 inhibitors promoted reduction of FLT3-ITD AML stem cells [21].These evidences indicated that inhibition of SIRT1 network combined with TKIs or FLT3 inhibitors could be an attractive approach for BCR-ABL CML and FLT3-ITD AML treatment.
In addition, low level of miR-34a and high level of its target SIRT1 were found in CD44 positive and CD24-negtive BCSCs, and further study showed that miR-34a inhibited proliferative potential of BCSCs and downregulated the expression of CSC markers aldehyde dehydrogenase 1 (ALDH1), polycomb ring finger proto-oncogene Bmi1 and homeobox transcription factor Nanog partially by downregulating SIRT1 (Figure 2) [18].Such mechanism might also occur in PCSCs [19].In addition, many colorectal cancer specimens had strong SIRT1 expression, which had an obvious correlation with poor prognosis of colorectal cancer patients.Besides, SIRT1 was highly expressed in colorectal CSC-like cells and its expression had a colocalization with CD133, a current common used marker of CCSCs.Further study showed that SIRT1 knockdown reduced proportion of CD133-positive cells, dampened colony and sphere formation in vitro, and restrained tumorigenicity in vivo.Importantly, the expressions of Oct4, Cripto, Nanog, telomerase reverse transcriptase (TERT) and Lin28, which are stemness-associated genes, were decreased by SIRT1 deficiency [17].These evidence indicated that SIRT1 played a crucial role in keeping the characteristics of stemness in colorectal cancer cells and SIRT1 may act as a potential prognostic factor of tumor recovery risk for cancer patients, and will contribute to providing a new therapeutic method for cancer treatment.SIRT2 was another deacetylase that is increasingly identified as a essential regulator of cell cycle, cellular necrosis and cytoskeleton reorganization [25].It's recently reported to play an important role in carcinogenesis [26] and early lineage commitment of embryonic stem cell [27].Recent research showed that SIRT2 could be induced by Notch signaling, thus leading to aldehyde dehydrogenase 1A1 (ALDH1A1) deacetylation and enzymatic activation to promote BCSCs (Figure 2) [28].SIRT2 was also highly expressed in CSCs and its activity is required for CSCs proliferation arrest induced by resveratrol, a potent SIRT1 inhibitor [29].However, in skin tumors but not normal skin, SIRT2 deletion up-regulates the stem cell marker CD34 [30].No doubt, much more exploration should be conducted to make sure the exactly role of SIRT2 in CSCs.
Other members of sirtuins also have been demonstrated to play an important role in tumorigenesis and cancer development [31].For example, SIRT3 limits reactive oxygen species (ROS) levels in cancer cell, thus induces the degradation of hypoxia inducible factor 1α (HIF-1α) and high level of SIRT3 may suppress intracellular acidification, inhibit Bcl2-associated X protein (BAX) activation and subsequent mitochondrial permeability transition (MPT) induction [32].SIRT4 inhibits mitochondrial glutamine metabolism and responses to deoxyribonucleic acid (DNA) damage in cancer cells [33].SIRT6 regulates glucose metabolism in tumors and acts as a tumor suppressor [34].SIRT7 deacetylates H3K18 and maintains oncogenic transformation [35].In addition, these sirtuins, especially SIRT6 [36,37], SIRT7 [38] and SIRT3 [39], also have been demonstrated to play important roles in the maintenance and differentiation of normal stem cells.They might also act as key regulators in CSCs, but their roles are remained to be further explored.
CSCs are a small subset of cells that are responsible for initiation, development, and recurrence of tumors.Therefore, it is important to understand the molecular mechanism of CSCs for translational applications using CSCs in the treatment of patients with cancer.Sirtuins are an important family of HDACs and have been shown to tightly relate to CSCs and play essential roles in the maintenance and self-renew properties of CSCs.These evidences indicated that sirtuins must be important pharmaceutical targets for cancer therapy.