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.

[1]  L. Guarente,et al.  Aging and disease: connections to sirtuins , 2010, Aging cell.

[2]  Karine Gilbert,et al.  The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors , 2009, Molecular and Cellular Biology.

[3]  M. Oshimura,et al.  SIRT2 downregulation confers resistance to microtubule inhibitors by prolonging chronic mitotic arrest , 2009, Cell cycle.

[4]  M. Fraga,et al.  Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect , 2009, Oncogene.

[5]  M. Washburn,et al.  The SIRT2 deacetylase regulates autoacetylation of p300. , 2008, Molecular cell.

[6]  Kwang Youl Lee,et al.  Acetylation of Sirt2 by p300 attenuates its deacetylase activity. , 2008, Biochemical and biophysical research communications.

[7]  X. Wang,et al.  Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. , 2008, Cancer cell.

[8]  F. Alt,et al.  Tissue-specific regulation of SIRT1 by calorie restriction. , 2008, Genes & development.

[9]  J. Denu,et al.  The Sirtuin family: therapeutic targets to treat diseases of aging. , 2008, Current opinion in chemical biology.

[10]  M. Tainsky,et al.  Mutations in SIRT2 deacetylase which regulate enzymatic activity but not its interaction with HDAC6 and tubulin , 2007, Molecular and Cellular Biochemistry.

[11]  M. Oshimura,et al.  SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress , 2007, Oncogene.

[12]  B. Delaval,et al.  Loss of centrosome integrity induces p38—p53—p21-dependent G1—S arrest , 2007, Nature Cell Biology.

[13]  L. Guarente,et al.  Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. , 2006, Genes & development.

[14]  F. Alt,et al.  SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. , 2006, Genes & development.

[15]  R. DePinho,et al.  Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. , 2006, Cancer research.

[16]  J. Ashwell,et al.  Activating p38 MAPK: New Tricks for an Old Kinase , 2005, Cell cycle.

[17]  S. Tachiiri,et al.  Role of NAD‐dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin‐induced cell death in vertebrate cells , 2005, Genes to cells : devoted to molecular & cellular mechanisms.

[18]  Myriam Gorospe,et al.  Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase , 2004, Science.

[19]  M. Mayo,et al.  Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase , 2004, The EMBO journal.

[20]  M. Swanson,et al.  Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10. , 2004, Journal of biochemistry.

[21]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[22]  Michael A. Tainsky,et al.  Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle , 2003, Molecular and Cellular Biology.

[23]  D. Livingston,et al.  Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300 , 2003, Science.

[24]  Y. Shiloh.  ATM and related protein kinases: safeguarding genome integrity , 2003, Nature Reviews Cancer.

[25]  Hua Lu,et al.  The Acetylase Activity of p300 Is Dispensable for MDM2 Stabilization* , 2003, The Journal of Biological Chemistry.

[26]  Clonal heterogeneity in differentiation potential of immortalized human mesenchymal stem cells. , 2002, Biochemical and biophysical research communications.

[27]  Delin Chen,et al.  Negative Control of p53 by Sir2α Promotes Cell Survival under Stress , 2001, Cell.

[28]  L. Kedes,et al.  Proteasome-Mediated Degradation of the Coactivator p300 Impairs Cardiac Transcription , 2000, Molecular and Cellular Biology.

[29]  K. Sakaguchi,et al.  Phosphorylation of human p53 by p38 kinase coordinates N‐terminal phosphorylation and apoptosis in response to UV radiation , 1999, The EMBO journal.

[30]  M. Lindsay,et al.  SB 203580, an inhibitor of p38 mitogen-activated protein kinase, enhances constitutive apoptosis of cytokine-deprived human eosinophils. , 1999, The Journal of pharmacology and experimental therapeutics.

[31]  Shuang Huang,et al.  Induction of Apoptosis by SB202190 through Inhibition of p38β Mitogen-activated Protein Kinase* , 1998, The Journal of Biological Chemistry.

[32]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[33]  T. Frebourg,et al.  Inactivation of p53 in normal human cells increases G2/M arrest and sensitivity to DNA‐damaging agents , 1998, International journal of cancer.

[34]  T. Horiuchi,et al.  p53 Antisense Oligonucleotide Inhibits Growth of Human Colon Tumor and Normal Cell Lines , 1996, Japanese journal of cancer research : Gann.

[35]  V. Iotsova,et al.  Antisense p53 provokes changes in HeLa cell growth and morphology. , 1995, European journal of cell biology.

[36]  Arnold J. Levine,et al.  The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 , 1990, Cell.

[37]  L. Guarente,et al.  Negative control of p53 by Sir2alpha promotes cell survival under stress. , 2001, Cell.