Activation of nuclear activation of SphK2 leads to formation of S1P, which inhibits HDAC1 and HDAC2, leading to increased histone acetylation p21 gene expression. In response to DNA damage (doxorubicin), p53 is upregulated, which leads to induction of BAX, NOXA, and PUMA (cell death mediators), and also induces p21, which suppresses apoptosis and induces cell cycle arrest. Downregulation of SphK2 prevents induction of p21 and removes p21-mediated protection against apoptosis, facilitating cell death.