Here, we demonstrate that TSPYL5 mediates the AKT/TSPYL5/PTEN signaling loop and that AKT-mediated phosphorylation of TSPYL5 persistently maintains cancer stemness via transcriptional activation of the CSC-associated genes, ALDH1 and CD44. Also, we show that TSPYL5 can potentially be used as a CSC target for cancer therapy. The gene discussed is CD44; the disease is cancer.