Abstract
The highest incidence of esophageal squamous cell carcinoma (ESCC) occurs in China. Cancer stem cells play key roles for tumor progression. Gene amplified in squamous cell carcinoma 1 (GASC1) is essential to maintain self-renewal and differentiation potential of embryonic stem cells. This study aimed to reveal the effect and mechanism of GASC1 on ESCC stemness. The biological function of GASC1 in ESCC was evaluated both in vitro and in vivo. ChIP assay was performed to determine the molecular mechanism of GASC1 in epigenetic regulation of NOTCH1. We found that GASC1 expression was increased in poor differentiated ESCC cells and tissues. ESCC patients with a high level of GASC1 presented a significantly worse survival rate. GASC1 expression in purified ALDH+ ESCC cells was significantly higher than that in ALDH− cells. The stemness of ESCC was dramatically decreased after GASC1 blockade. Furthermore, blockade of GASC1 decreased NOTCH1 expression via increase of NOTCH1 promoter H3K9me2 and H3K9me3. Moreover, the impaired stemness after blockade of GASC1 could be reversed after transfection of NOTCH1 overexpression lentiviral vector. GASC1 promoted stemness in ESCC cells via NOTCH1 promoter demethylation. Therefore, GASC1/NOTCH1 signaling might be a potential therapeutic target for the treatment of ESCC patients.
Highlights
Esophageal cancer (EC) is the eighth most common cancer worldwide and the sixth leading cause of cancer-related deaths
The results showed that mRNA expression of Gene amplified in squamous cell carcinoma 1 (GASC1) in KYSE30 and KYSE150 cells was significantly higher than that in SHEE, KYSE70, and KYSE140 cells (P
GASC1 is overexpressed in many types of tumors including breast cancer [14], esophageal squamous cell carcinoma (ESCC) [15], metastatic sarcomatoid carcinoma in lung, and primary mediastinum B cell lymphoma and Hodgkin’s lymphoma [16]
Summary
Esophageal cancer (EC) is the eighth most common cancer worldwide and the sixth leading cause of cancer-related deaths. China is the country with the highest incidence of EC in the world [1]. Contrary to European and American countries that 80% of EC is adenocarcinoma, more than 90% of EC in China is esophageal squamous cell carcinoma (ESCC). Few new small-molecule targeted drugs are explored for advanced ESCC in some clinical trials, there still are no strong evidences that support the patients would have satisfactory survival. Cancer stem cells (CSCs) are responsible for cancer growth, metastasis, and recurrence [2].
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