Effect of TET1 regulating MGMT on chemotherapy resistance of oral squamous cell carcinoma stem cells

Abstract

The study was to evaluate the effect of ten-eleven translocation 1 (TET1) regulating o6-methylguanine-DNA methyltransferase (MGMT) in chemotherapy resistance of oral squamous cell carcinoma (OSCC) stem cells. OSCC stem cells were divided into the blank, negative control (NC), TET1-siRNA, TET1-siRNA + MGMT-OE, and MGMT-OE groups. Methylation-specific polymerase chain reaction (MSP), qRT-PCR and Western blotting were conducted to detect the methylation status of MGMT, expressions of TET1, MGMT, ABCG2, and Oct-4. Cell proliferation, cisplatin chemosensitivity, and cell cycle and apoptosis, were detected using CCK8 and flow cytometry. A chromatin immunoprecipitation (ChIP) assay was employed for detecting the link between TET1 and MGMT gene promoters. In comparison to the NC group, the TET1-siRNA group exhibited increased levels of MGMT methylation, the number of apoptotic cells and cisplatin chemosensitivity consisting of varying concentrations, however, decreased levels of mRNA and protein expressions of TET1 as well as MGMT, cell viability, the number of cells in the S phase, and protein expressions of ABCG2 and Oct-4 were all have diminished amounts. The TET1-siRNA + MGMT-OE and MGMT-OE groups had higher MGMT mRNA and protein expression, as well as increased protein expressions of ABCG2 and Oct-4, greater cell activity, higher number of cells in the S phase, decreased apoptotic rates in cells and decreased cisplatin chemosensitivity with different concentrations. Our study provided evidence that low-expression of TET1 in OSCC stem cells may stimulate MGMT promoter methylation, while inhibiting MGMT mRNA expression, this ultimately strengthens the sensitivity of OSCC stem cells in regards to chemotherapeutics. K E Y W O R D Schemotherapy resistance, human oral squamous cell carcinoma, MGMT, Tca8113 cell line, TET1

<p>Demethylation and Overexpression of CSF2 are Involved in Immune Response, Chemotherapy Resistance, and Poor Prognosis in Colorectal Cancer</p>

“…[28][29][30][31] Several studies have reported that dysregulation of DNA methylation can promote oncogene expression and chemotherapy resistance. [32][33][34] In the present study, we found CSF2 demethylation in the promoter sites in both colon and rectal cancer tissues. These results suggested that CSF2 demethylation resulted in increased CSF2 expression in CRC.…”

Epigenetic Modifications in Head and Neck Cancer

“…Furthermore, higher levels of TET and PML were associated with better overall survival of HNSCC patients (Song et al 2018). Wang et al (2018b) showed that a decreased expression of TET-1 in OSCC may lead to increased promoter methylation of MGMT, and enhanced the sensitivity of OSCC stem cells to chemotherapeutics like cisplatin.…”

Enhanced expression of ten‐eleven translocation 1 reverses gemcitabine resistance in cholangiocarcinoma accompanied by a reduction in P‐glycoprotein expression

“…Xi Han et al found that TET1 expression resulted in resistance to cisplatin, and that one of the targets of TET1 action was vimentin involved in partial epithelial‐to‐mesenchymal (EMT) in ovarian cancer . Wei Wang et al provided evidence that decreased expression of TET1 may strengthen the sensitivity of oral squamous cell carcinoma stem cells to chemotherapeutics by stimulating MGMT promoter methylation to suppress MGMT mRNA expression . However, research revealed that gemcitabine‐resistant CCA cells displayed not only MDR but also enhanced invasiveness .…”