Collectively, our data indicated that (i) YB-1 is a key transcription factor that maintains the stemness of cancer stem cells by promoting the expression of stemness-related genes (FZD-1, p21, GLP-1, GINS1, and Notch2) and (ii) YB-1 plays a requisite role in the activation and reversion of the totipotency or pluripotency of differentiated cancer cells. The gene discussed is YBX1; the disease is cancer.