SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-dependent p300 decrease, eventually leading to apoptosis.
We previously reported that sirtuin 2 (SIRT2), a mammalian member of the NAD+-dependent protein deacetylases, participates in mitotic regulation, specifically, in efficient mitotic cell death caused by the spindle checkpoint. Here, we describe a novel function of SIRT2 that is different from mitotic regulation. SIRT2 down-regulation using siRNA caused apoptosis in cancer cell lines such as HeLa cells, but not in normal cells. The apoptosis was caused by p53 accumulation, which is mediated by p38 MAPK activation-dependent degradation of p300 and the subsequent MDM2 degradation. Sirtuin inhibitors are emerging as antitumor drugs, and this function has been ascribed to the inhibition of SIRT1, the most well-characterized sirtuin that deacetylases p53 to promote cell survival and also binds to other proteins in response to genotoxic stress. This study suggests that SIRT2 can be a novel molecular target for cancer therapy and provides a molecular basis for the efficacy of SIRT2 for future cancer therapy.
Division of Human Genome Science, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
Yanze
Y
Li
Haruka
H
Matsumori
Yuji
Y
Nakayama
Mitsuhiko
M
Osaki
Hirotada
H
Kojima
Akihiro
A
Kurimasa
Hisao
H
Ito
Seiichi
S
Mori
Motonobu
M
Katoh
Mitsuo
M
Oshimura
Toshiaki
T
Inoue
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D056565:Sirtuin 2; D037761:Sirtuins