We identified tumor initial cells (TICs) from a number of ESCC cell lines and demonstrated increased expression of GASC1 in the ESCC ALDH + TICs and its involvement in TICs maintenance by specific demethylation of H3K9Me3 at the SOX2 and NOTCH1 promoter. Here, NOTCH1 is linked to esophageal squamous cell carcinoma.