DNMT1 ablation suppresses tumorigenesis by inhibiting the self-renewal of esophageal cancer stem cells

Abstract

Cancer stem cells (CSCs) have been isolated from many tumors and considered as the main reason of cancer recurrence and metastasis. DNA methyltransferase 1 (DNMT1) mediates DNA methylation and plays an important role in CSCs maintenance. However, the function of DNMT1 in CSCs of esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we examined the role of DNMT1 in regulating self-renewal in CSCs of ESCC. We found a high expression of DNMT1 in both side population (SP) cells and sphere formation cells that represented as substitutes for CSCs in KYSE150 and EC109 ESCC cell lines. We performed the knockdown of DNMT1 using lentivirus-mediated RNA interference (RNAi) methods. We revealed that ablation of DNMT1 resulted in the numbers and self-renewal abilities of CSCs refrained significantly in ESCC cells. As a result of the CSCs inhibition, the malignant phenotypes such as cell proliferation, colony formation, migration and drug resistance abilities were dramatically inhibited in ESCC cells. Treatment of 5-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor, also resulted in the inhibition of CSCs and malignant profiles in ESCC cells. Our findings also provided the first evidence that 5-aza-dC inhibited the colony and sphere formation of CSCs. Thus, our results indicated that DNMT1 was important for the self-renewal maintenance of CSCs in ESCC, and 5-aza-dC could be a potential therapy for the CSCs of ESCC.

RETRACTED: LINC00184 silencing inhibits glycolysis and restores mitochondrial oxidative phosphorylation in esophageal cancer through demethylation of PTEN

“…Consistently, epigenetic silencing of PTEN gene by promoter hypermethylation is frequently demonstrated as a significant mechanism of PTEN deletion in ESCC [11]. Moreover, DNMT1, a member of the DNA methyltransferase family and a regulator of DNA methylation, is responsible for maintaining self-renewal maintenance of EC stem cells [31,32]. Specifically, it has been postulated that loss of DNMTs, particularly DNMT1, may contribute to a decline of promoter hypermethylation, which leads to restoration of PTEN in activated hepatic stellate cells [33].…”

Identification of Key Modules and Hub Genes Involved in Esophageal Squamous Cell Carcinoma Tumorigenesis Using WCGNA

“… 25 DNMT1 is also a key regulator of methylation status in the context of stem cell maintenance and embryogenesis. 26 NCAPG is a condensin I complex subunit that regulates chromosome condensation and stabilization in the context of mitosis and meiosis. NCAPG overexpression has been detected in cancers including melanoma, lung cancer, prostate cancer, and HCC, suggesting that this gene plays an important oncogenic role.…”

Targeting Ovarian Cancer Stem Cells by Dual Inhibition of HOTAIR and DNA Methylation

“…The synergistic effect of inhibiting both DNMT1-HOTAIR indicates that the drugs may be targeting the products of genes in parallel and highly connected pathways. DNMTs regulate EMT process and CSCs phenotypes in various cancers (40), and regulators of DNMT1 were involved in these process, such as miRNAs, oncogenes, and cytokines (41)(42)(43). HOTAIR and DNMT1 interaction in several cancers has been shown (44,45), and HOTAIR knockdown downregulates DNMT1 and decreases DNA methylation on both a global level as well as at gene promoters (44).…”