TP53 and cancer: Several previous studies have suggested that SIRT2 has complex regulating mechanisms promoting or inhibiting apoptosis.242 In contrast to SIRT1, SIRT2 is predominantly a cytoplasmic protein and is able to deacetylate several cytoplasmic substrates,243 including p53,244 NF-κB,245 and FoxO3.246 In terms of its anti-apoptotic effects, SIRT2 downregulation alone is sufficient to cause apoptosis, and SIRT2 depletion leads to p53 accumulation causing activation of the p38 MAPK in cancer cell lines such as HeLa, but not in normal cells.247