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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.

SUBMITTER: Teng Y

PROVIDER: S-EPMC5922364 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Teng Ying Y Yu Xiying X Yuan Hui H Guo Liping L Jiang Wei W Lu Shih-Hsin SH

Oncotarget 20180102 27

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 a ...[more]

PMID: 29721170

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Project description:Self-renewal of embryonic stem cells (ESCs) is orchestrated by a vast number of genes at the transcriptional and translational levels. However, the molecular mechanisms of post-translational regulatory factors in ESC self-renewal remain unclear. Histidine phosphorylation, also known as hidden phosphorylation, cannot be detected by conventional experimental methods. A recent study defined phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) as a histidine phosphatase, which regulates various biological behaviors in cells via histidine dephosphorylation. In this study, the doxycycline (DOX)-induced hLHPP-overexpressing mouse ESCs and mouse LHPP silenced mESCs were constructed. Quantitative polymerase chain reaction (qPCR), western blotting analysis, immunofluorescence, Flow cytometry, colony formation assays, alkaline phosphatase (AP) and bromodeoxyuridine (Brdu) staining were performed. We found that the histidine phosphorylation level was strikingly reduced following LHPP overexpression. Besides, the expression of Oct4 and Lefty1, indispensable genes in the process of ESCs self-renewal, was significantly down-regulated, while markers related to the differentiation were markedly elevated. Moreover, LHPP-mediated histidine dephosphorylation induced G0/G1 phase arrest in mESCs, suggesting LHPP was implicated in cell proliferation and cell cycle. Conversely, silencing of Lhpp promoted the self-renewal of mESCs and reversed the RA induced increased expression of genes associated with differentiation. Mechanistically, our findings suggested that the enzymatic active site of LHPP was the cysteine residue at position 226, not 53. LHPP-mediated histidine dephosphorylation lowered the expression levels of β-catenin and the cell cycle-related genes CDK4 and CyclinD1, while it up-regulated the cell cycle suppressor genes P21 and P27. Taken together, our findings reveal that LHPP-mediated histidine dephosphorylation plays a role in the self-renewal of ESCs. LHPP-mediated histidine dephosphorylation inhibited the self-renewal of ESCs by negatively regulating the Wnt/β-catenin pathway and downstream cell cycle-related genes, providing a new perspective and regulatory target for ESCs self-renewal.

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

Publications

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

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