Modulation of p21 influenced cell-cycle re-entry, senescence burden, and responsiveness to PTX.<h4>Conclusions</h4>These findings define an HDAC-p21-senescence axis that sustains chemoresistance in bladder cancer and provide preclinical evidence supporting combined epigenetic and antimitotic therapy as a strategy to overcome acquired drug tolerance. This evidence concerns the gene HDAC9 and urinary bladder cancer.