SIRT1 Is Significantly Elevated in Mouse and Human Prostate Cancer

Abstract

Evidence suggests that the histone deacetylase, SIRT1, is a mediator of life span extension by calorie restriction; however, SIRT1 may paradoxically increase the risk of cancer. To better understand the relationship among SIRT1, energy balance, and cancer, two experiments were done. First, a transgenic mouse model of prostate cancer (transgenic adenocarcinoma of mouse prostate; TRAMP) was used to determine the role of energy balance on SIRT1 expression and the effect of cancer stage on SIRT1 and hypermethylated in cancer-1 (HIC-1). Second, immunohistochemistry was done on human prostate tumors to determine if SIRT1 was differentially expressed in tumor cells versus uninvolved cells. Results show that SIRT1 is not increased in the dorsolateral prostate (DLP) of calorierestricted mice during carcinogenesis. In contrast, when examined in the DLP as a function of pathologic score, SIRT1 was significantly elevated in mice with poorly differentiated adenocarcinomas compared with those with less-advanced disease. HIC-1, which has been shown to regulate SIRT1 levels, was markedly reduced in the same tumors, suggesting that a reduction in HIC-1 may be in part responsible for the increased expression of SIRT1 in prostatic adenocarcinomas. Furthermore, immunostaining of human prostate tumors showed that cancer cells had greater SIRT1 expression than uninvolved cells. In conclusion, DLP SIRT1 expression from calorie-restricted mice was not altered during carcinogenesis. However, SIRT1 expression was increased in mice with poorly differentiated adenocarcinomas and in human prostate cancer cells. Because SIRT1 may function as a tumor promoter, these results suggest that SIRT1 should be considered as a potential therapeutic target for prostate cancer. [Cancer Res 2007;67(14):6612-8]

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

“…Our work shows that SIRT1 promotes prostate cancer cell growth and survival, consistent with its overexpression in primary human and mouse prostate cancers (Huffman et al, 2007;Jung-Hynes et al, 2009). Our results are in-line with findings from other groups (Kojima et al, 2008;Jung-Hynes et al, 2009).…”

“…SIRT1 is overexpressed in primary human prostate cancer and mouse models of prostate cancer (Huffman et al, 2007;Jung-Hynes et al, 2009). However, roles of SIRT1 in prostate cancer remain controversial as two groups show that SIRT1 promotes prostate cancer cell growth and survival (Kojima et al, 2008;Jung-Hynes et al, 2009) whereas the other two groups show the opposite effect (Fu et al, 2006;Dai et al, 2007).…”

“…SIRT1 is overexpressed in multiple primary solid tumors and hematopoietic malignancies (Bradbury et al, 2005;Huffman et al, 2007;Jang et al, 2008Jang et al, , 2009Jung-Hynes et al, 2009;Nosho et al, 2009). Inhibition of SIRT1 suppresses growth and promotes apoptosis in human cancer cells (Luo et al, 2001;Vaziri et al, 2001;Chu et al, 2005;Ford et al, 2005;Ota et al, 2006;Kojima et al, 2008;Jung-Hynes et al, 2009), but has little impact on the survival of normal cells (Ford et al, 2005;Jung-Hynes et al, 2009).…”

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

“…SIRT1 expression is significantly elevated in prostate and colon cancers (Huffman et al, 2007;Stunkel et al, 2007), and HIC1 (hypermethylated in cancer 1), an inhibitor of SIRT1 transcription, is epigenetically silenced in many tumors (Chen et al, 2005). SIRT1 has however in addition to H4K16 been shown to be a protein deacetylase, and plural effects of SIRT1 on cell survival have been reported.…”

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…Accumulating evidence also point to SirT1 as having a function in cancer; however, inferences from the literature are that SirT1 has both oncogenic and tumor-suppressor activities. SirT1 was reported to be overexpressed in acute myeloid leukemia, non-melanoma skin cancer, breast cancer, colorectal carcinoma and prostate cancer (Bradbury et al, 2005;Kuzmichev et al, 2005;Hida et al, 2007;Huffman et al, 2007;Stunkel et al, 2007) and to be downregulated in glioblastoma, prostate cancer, bladder carcinoma, breast cancer, hepatocellular carcinoma and ovarian cancer (Wang et al, 2008a). It is also expressed at a high level in diffuse large B-cell lymphomas and is associated to bad prognosis (Jang et al, 2008).…”