Function of the SIRT1 protein deacetylase in cancer

• Published in: Biotechnology journal 2007-11, Vol.2 (11), p.1360-1368
• Main Authors: Stünkel, Walter, Peh, Bee Keow, Tan, Yong Cheng, Nayagam, Vasantha M., Wang, Xukun, Salto-Tellez, Manuel, Ni, BinHui, Entzeroth, Michael, Wood, Jeanette
• Format: Article
• Language: English
• Subjects: Apoptosis - genetics; Apoptosis - physiology; Cell Line, Tumor; Cell Proliferation; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytosol - metabolism; Deacetylase; DNA Damage; Gene Expression Regulation, Neoplastic; HeLa Cells; High-throughput screen; Humans; Immunohistochemistry; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Overexpression; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; SIRT1; Sirtuin 1; Sirtuins - genetics; Sirtuins - metabolism; Tissue Array Analysis; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1860-6768; 1860-7314
• DOI: 10.1002/biot.200700087

The NAD+‐dependent protein deacetylase SIRT1 is linked to cellular survival pathways by virtue of keeping the tumor suppressor gene p53 and members of the forkhead transcription factor family deacetylated. To validate SIRT1 as a therapeutic anti‐cancer target, we performed immunohistochemistry experiments to study the in vivo expression of SIRT1 in cancer specimens. We show that human SIRT1 is highly expressed in cancer cell lines as well as in tissue samples from colon carcinoma patients. Interestingly, there is a strong cytosolic component in the SIRT1 expression pattern. We further characterized SIRT1 in p53‐wild‐type and ‐mutant cell lines and show that SIRT1 mRNA‐knockdown leads to a p53‐independent decrease of cell proliferation and induction of apoptosis. In addition, SIRT1 expression has been found to be inducible upon DNA damage. A previously discovered small molecule SIRT1 inhibitor with nanomolar in vitro activity has been tested in cancer relevant assays. The SIRT1 inhibitory compound showed no potent anti‐proliferative activity despite hitting its molecular target within tumor cells. From these studies we conclude that it may not be sufficient to block the catalytic function of SIRT1, and that its survival effects may be mainly brought about by means other then the deacetylase function. The increased cytosolic expression of SIRT1 in cancer cells could be an indicator of such novel functions.