SIRT1 (silent mating-type information regulation 2 homologue 1)-mediated cellular resistance to various stresses is negatively regulated by deleted in breast cancer 1 (DBC1), which was originally reported to be deleted in breast cancer. However, the suggested functions of SIRT1 as a potential tumor promoter and of DBC1 as a potential tumor suppressor have been challenged by observations of their respective down-and up-regulation in various cancers. The aim of the present study was to simultaneously evaluate the expression levels of SIRT1 and DBC1 in the normal and tumor breast tissues from 28 breast cancer patients and to determine correlations with clinicopathological variables. SIRT1 and DBC1 expression was higher in tumor tissues than in matched normal tissues at the protein level, but not at the transcriptional level. Overexpression of SIRT1 and DBC1 in tumor tissue was correlated with favorable and unfavorable clinicopathological factors, suggesting their pleiotropic functions as a potential tumor promoter and tumor suppressor in tumorigenesis. Interestingly, although the overall expression of SIRT1 and DBC1 increased in tumor breast tissues, the correlation between SIRT1 and DBC1 expression was weaker in tumor tissue than in normal tissue. This suggests that the negative regulation of SIRT1 by DBC1 may retard tumorigenesis in breast tissue. Therefore, the correlation between SIRT1 and DBC1 is a potential prognostic indicator in breast cancer. (Cancer Sci 2010; 101: 1738-1744 S IRT1 is a protomember of the sirtuin family (SIRT1-7) that deacetylates histones and numerous non-histone substrates in a nicotinamide adenine dinucleotide (NAD + )-dependent manner.(1) SIRT1 (silent mating-type information regulation 2 homologue 1) participates in a variety of physiological processes, such as gene silencing, metabolism, neuroprotection, and genomic stability.(1,2) In regards to growth of cancer cells, it has been reported that SIRT1 regulates cell proliferation, survival, and death, and plays a pivotal role in tumorigenesis.Several studies have demonstrated a significant increase in SIRT1 in human prostate cancer, (3) ovarian cancer,gastric cancer, (5) colon cancer, (6,7) breast cancer, (8,9) glioblastoma,lymphoma, (11) acute myeloid leukemia, (12) and non-melanoma skin cancers.(13) On a molecular level, SIRT1 promotes cellular survival by deacetylating cell cycle regulators, including p53, (14) p73, (15) Rb, (16) and FOXOs, (17) or represses the transcription of tumor suppressors such as E-cadherin and MLH1.(18) SIRT1 inhibition sensitizes cells to ionizing radiation and chemotherapeutic reagents such as cisplatin, and reverses drug resistance.(19-21) These findings support the potential role of SIRT1 as a tumor promoter.In contrast, SIRT1 in transgenic mice retards colon cancer growth as SIRT1 deacetylates b-catenin and promotes its cytoplasmic localization, (22) and increases overall survival in p53mice. (23) In addition, SIRT1 induces tumor necrosis factor (TNF)-a-induced apoptosis through the deacetylation of ...

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CCAR2 (cell cycle and apoptosis regulator 2) controls a variety of cellular functions; however, its main function is to regulate cell survival and cell death in response to genotoxic and metabolic stresses. Recently, we reported that CCAR2 protects cells from apoptosis following mitochondrial stress, possibly by co-operating with Hsp60. However, it is not clear how CCAR2 and Hsp60 control cell survival and death. Here, we found that depleting CCAR2 and Hsp60 downregulated expression of survivin, a member of the inhibitor of apoptosis (IAP) family. Survivin expression in neuroblastoma tissues and human cancer cell lines correlated positively with expression of CCAR2 and Hsp60. Furthermore, high expression of CCAR2, Hsp60, and survivin was associated with poor survival of neuroblastoma patients. In summary, both CCAR2 and Hsp60 are required for expression of survivin, and both promote cancer cell survival, at least in part, by maintaining survivin expression. Therefore, CCAR2, Hsp60, and survivin are candidate tumor biomarkers and prognostic markers in neuroblastomas.

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