Two mechanisms underlying the loss of p16Ink4a function are associated with distinct tumorigenic consequences for WS MEFs escaping from senescence

► p16Ink4a status from tumorigenic or non-tumorigenic cells escaping from senescence. ► Overexpression of p21Waf1/Cip1 demethylated p16Ink4a and restored cellular senescence. ► p16Ink4a and adjacent genes are deleted in non-tumorigenic immortalized cells. ► The functional loss of p16Ink4aper se might not be sufficient for tumorigenesis. ► The data shed light on the strategy of anti-aging by regulating p16Ink4a expression.