We found that acetylation of K75 mediated by acetyl-CoA synthetase 2 (ACSS2)/p300, along with deacetylation mediated by the miR29a-HDAC4 axis and O-GlcNAcylation of S246, are involved in regulating the stability of Sox2 during CRC progression. Here, HDAC4 is linked to colorectal carcinoma.