p21Waf1 is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate

Cell senescence is characterized by senescent morphology and permanent loss of proliferative potential. HDAC inhibitors (HDACI) induce senescence and/or apoptosis in many types of tumor cells. Here, we studied the role of cyclin-kinase inhibitor p21waf1(Cdkn1n gene) in cell cycle arrest,   senescence markers (cell hypertrophy, SA-bGal staining and accumulation of gH2AX foci) in p21Waf1+/+ versus p21Waf1-/- mouse embryonic fibroblast cells transformed with E1A and cHa-Ras oncogenes (mERas). While short treatment with the HDACI sodium butyrate (NaB) induced a reversible G1 cell cycle arrest in both parental and p21Waf1-/- cells, long-term treatment led to dramatic changes in p21Waf1+/+ cells only: cell cycle arrest became irreversible and cells become hypertrophic,  SA-bGal-positive and accumulated gH2AX foci associated with mTORC1 activation. The p21Waf1+/+ cells lost their ability to migrate into the wound and through a porous membrane. Suppression of migration was accompanied by accumulation of vinculin-...