In conclusions, our data demonstrate that (a) SATB2 is highly expressed in HCC cells derived from AA compared with those from CA, (b) inhibition of SATB2 in HCC cells derived from both AA and CA origins attenuates cell proliferation, colony formation, spheroid formation and EMT, and (c) SATB2 regulates CSC characteristics by modulating the expression of stem cell markers (CD133, CD44 and CD24), pluripotency maintaining factors (c‐Myc, KLF4, SOX2 and OCT4) and EMT transcription factors (Snail, Slug and Zeb1). Here, POU5F1 is linked to hepatocellular carcinoma.