Expression of SIRT1 and DBC1 Is Associated with Poor Prognosis of Soft Tissue Sarcomas

Kim, Jung Ryul; Moon, Young Jae; Kwon, Keun Sang; Bae, Jong Seok; Wagle, Sajeev; Yu, Taek Kyun; Kim, Kyoung Min; Park, Ho Sung; Lee, Ju-Hyung; Moon, Woo Sung; Lee, Ho; Chung, Myoung Ja; Jang, Kyu Yun

doi:10.1371/journal.pone.0074738

Cited by 55 publications

(70 citation statements)

References 52 publications

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“…Indeed, regulation of p53 by CCAR2 appears to be important for tumor initiation in some tissues, as Ccar2 −/− mice have increased tumor incidence compared to wild-type controls, dependent on p53 but Sirt -independent (Qin et al , 2015). In contrast to this data, many tumor types have been reported to have high expression of CCAR2, and this correlates with poor clinical outcomes (Cha et al , 2009; Cho et al , 2015; Kim et al , 2013; Kim et al , 2012; Yu et al , 2015; Yu et al , 2013; Zhang et al , 2014). In addition, the large majority of SCC tumors have mutated or lost p53 (Giglia-Mari and Sarasin, 2003), while CCAR2 is rarely altered in human cancer (Cerami et al , 2012), suggesting there may be p53-independent roles for CCAR2 in SCC.…”

Section: Discussioncontrasting

confidence: 74%

“…Clinical studies across a variety of tumor types, including SCC, have suggested that high levels of CCAR2 ( C ell C ycle activator and A poptosis R egulator 2; also known as DBC1) may be an indicator of poor outcomes (Chen et al , 2014; Kim et al , 2013; Kim et al , 2012; Yu et al , 2013), and could potentially have pro-tumorigenic functions. However, studies in Ccar2 − / − mice suggest that Ccar2 may function as a tumor-suppressor, although SCC did not develop in these mice (Qin et al , 2015).…”

Section: Intoductionmentioning

confidence: 99%

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CCAR2 Is Required for Proliferation and Tumor Maintenance in Human Squamous Cell Carcinoma

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Nwaobasi

Schmults

et al. 2017

Journal of Investigative Dermatology

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CCAR2 is a widely expressed protein involved in the regulation of a variety of transcriptional complexes. High expression of CCAR2 correlates with poor outcomes in a variety of human tumor types such as Squamous Cell Carcinoma (SCC). Paradoxically, loss of Ccar2 in the mouse results in an increased tumor burden, suggesting that CCAR2 may in fact function as a tumor suppressor. Importantly, this tumor suppressor function is dependent on p53, a protein that is inactivated in the vast majority of SCC tumors, leaving the role of CCAR2 in p53-null tumors unclear. We sought to identify p53-independent CCAR2 functions in Squamous Cell Carcinoma, and to examine its role in tumorigenesis. We find that CCAR2 is highly over-expressed in p53-deficient SCC cell lines compared to normal primary keratinocytes due to increased protein stability. We identify a role for CCAR2 in promoting the stability of the transcription factors RFX1 and CREB1, which are both required for proliferation. Finally, we demonstrate that CCAR2 is required for proliferation in vitro and in established SCC tumors in vivo. Our data suggest an important role for CCAR2 in maintaining cell cycle progression and promoting SCC tumorigenesis.

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Section: Discussioncontrasting

confidence: 74%

Section: Intoductionmentioning

confidence: 99%

CCAR2 Is Required for Proliferation and Tumor Maintenance in Human Squamous Cell Carcinoma

Best

Nwaobasi

Schmults

et al. 2017

Journal of Investigative Dermatology

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“…SIRT1 is also overexpressed in non-melanoma skin cancers, including squamous and basal cell carcinomas, actinic keratosis, and especially in Bowen's disease [16]. Further, the overexpression of SIRT1 has been linked to poor disease prognosis and survival in variety of cancers [17-19]. However, the role of SIRT1 is quite puzzling as there is an ongoing debate regarding its role as a tumor suppressor versus tumor promoter [20].…”

Section: Introductionmentioning

confidence: 99%

Novel downstream molecular targets of SIRT1 in melanoma: A quantitative proteomics approach

et al. 2014

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Melanoma is one of the most lethal forms of skin cancer and its incidence is continuing to rise in the United States. Therefore, novel mechanism and target-based strategies are needed for the management of this disease. SIRT1, a NAD(+)-dependent class III histone deacetylase, has been implicated in a variety of physiological processes and pathological conditions. We recently demonstrated that SIRT1 is upregulated in melanoma and its inhibition by a small-molecule, tenovin-1, inhibits cell proliferation and clonogenic survival of melanoma cells, possibly via activating p53. Here, we employed a gel free quantitative proteomics approach to identify the downstream effectors and targets of SIRT1 in melanoma. The human malignant melanoma, G361 cells were treated with tenovin-1 followed by protein extraction, in liquid trypsin digestion, and peptide analyses using nanoLC-MS/MS. A total of 1091 proteins were identified, of which 20 proteins showed significant differential expression with 95% confidence interval. These proteins were subjected to gene ontology and Ingenuity Pathway Analysis (IPA) to obtain the information regarding their biological and molecular functions. Real-Time qRT-PCR validation showed that five of these (PSAP, MYO1B, MOCOS, HIS1H4A and BUB3) were differentially expressed at mRNA levels. Based on their important role in cell cycle regulation, we selected to focus on BUB family proteins (BUB3, as well as BUB1 and BUBR1) for subsequent validation. The qRT-PCR and immunoblot analyses showed that tenovin-1 inhibition of SIRT1 resulted in a downregulation of BUB3, BUB1 and BUBR1 in multiple melanoma cell lines. Since tenovin-1 is an inhibitor of both SIRT1 and SIRT2, we employed lentivirus mediated silencing of SIRT1 and SIRT2 in G361 cells to determine if the observed effects on BUB family proteins are due to SIRT1- or SIRT2- inhibition. We found that only SIRT1 inhibition resulted in a decrease in BUB3, BUB1 and BUBR1. Our study identified the mitotic checkpoint regulator BUB family proteins as novel downstream targets of SIRT1. However, further validation is needed in appropriate models to confirm our findings and expand on our observations.

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“…It has been indicated that SIRT1-defective or knockdown cells have an increased apoptotic response to DNA damage or oxidative stress treatments (12 indicated a role for SIRT1 in tumorigenesis, its role in cancer has not been sufficiently studied. For example, SIRT1 demonstrates anti-oncogene action in colon cancer and its expression level is associated with prognosis, but it is considered to exhibit oncogenic action in breast cancer (13,14). A previous study indicated that tumors in SIRT1-deficient mice have markedly increased numbers of cells undergoing apoptosis (15).…”

Section: Introductionmentioning

confidence: 99%

miR-34a inhibits cell proliferation in prostate cancer by downregulation of SIRT1 expression

Duan

Zhang

et al. 2015

Oncology Letters

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Abstract. MicroRNA-34a (miR-34a) functions as a tumor suppressor gene and inhibits abnormal cell growth by regulating the expression of other genes. The role of miR-34a in regulating sirtuin 1 (SIRT1) in prostate cancer remains unclear. The objective of the present study was to investigate the biological function and molecular mechanisms of miR-34a regulation of SIRT1 in human prostate cancer samples and the human prostate cancer cell line, PC-3. Fresh prostate tissues were obtained from patients, and the miR-34a expression in prostate cancer tissues was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). qPCR and western blotting were performed to assess the effects of miR-34a overexpression on SIRT1 regulation in PC-3 cells, and the cell growth was assessed by Cell Counting Kit-8 (CCK-8). Flow cytometry was used to assess the cell cycle status of the cells. The miR-34a expression levels in prostate cancer tissues were significantly reduced compared with adjacent normal prostate tissues (P<0.05). SIRT1 expression levels in PC-3 cells with over-expression of miR-34a were significantly reduced compared with those in the negative control (P<0.05). The over-expression of miR-34a inhibited PC-3 cells growth and resulted in increased cell cycle arrest compared with the negative control (P<0.05). In conclusion, miR-34a inhibits the human prostate cancer cell proliferation, in part, through the downregulation of SIRT1 expression.

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Expression of SIRT1 and DBC1 Is Associated with Poor Prognosis of Soft Tissue Sarcomas

Cited by 55 publications

References 52 publications

CCAR2 Is Required for Proliferation and Tumor Maintenance in Human Squamous Cell Carcinoma

CCAR2 Is Required for Proliferation and Tumor Maintenance in Human Squamous Cell Carcinoma

Novel downstream molecular targets of SIRT1 in melanoma: A quantitative proteomics approach

miR-34a inhibits cell proliferation in prostate cancer by downregulation of SIRT1 expression

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