Abstract
BackgroundIncreasing evidence suggests that aberrant methylation is involved in 5-fluorouracil (5-FU) resistance in gastric cancer (GC). Our previous work has identified that Methyl-CpG binding protein 2 (MeCP2) promotes GC progression by binding to the methylation sites of promoter regions of specific genes to affect the downstream signaling pathways. However, the function and molecular mechanisms of MeCP2 in GC 5-FU resistance remain unclear.MethodsWe detected the expression of MeCP2 in 5-FU-resistant GC cells and examined cell behaviors when MeCP2 was silenced. The molecular mechanisms were explored through chromatin immunoprecipitation (ChIP)-qRT-PCR, luciferase reporter assay, clinical tissue samples analysis, and in vivo tumorigenicity assay.ResultsMeCP2 was up-regulated in 5-FU-resistant GC cells. Knockdown of MeCP2 enhanced the sensitivity of the cells to 5-FU. Moreover, MeCP2 promoted NOX4 transcription in the cells by binding to the promoter of NOX4. Silencing NOX4 rescued the inductive effect of MeCP2 overexpression on 5-FU sensitivity of GC cells and reduced the expression of NOX4 and PKM2 in MeCP2 overexpressed 5-FU-resistant GC cells. In addition, our in vivo experiments demonstrated that MeCP2 knockdown enhanced 5-FU sensitivity in tumors.ConclusionMeCP2 confers 5-FU resistance in GC cells via upregulating the NOX4/PKM2 pathway, which may lead to a promising therapeutic strategy for GC.
Highlights
Increasing evidence suggests that aberrant methylation is involved in 5-fluorouracil (5-FU) resistance in gastric cancer (GC)
We have found that Methyl-CpG binding protein 2 (MeCP2) promotes GC cell proliferation through FOXF1-mediated Wnt5a/β-Catenin signaling pathway and suppresses cell apoptosis through MYOD1-mediated Caspase-3 signaling pathway [15], or facilitates GC cell proliferation through activation of the MEK1/2-ERK1/2 signaling pathway by upregulating GIT1 [16], and it regulates glycogenes directly or indirectly to alter glycopatterning and affect GC cell proliferation and apoptosis [17]
MeCP2 was up‐regulated in 5‐FU‐resistant GC cells To capture the potential difference in MeCP2 expression between GC cells and 5-FU-resistant GC cells, qRT-PCR and western blot were conducted to measure the level of MeCP2 in BGC-823, SGC-7901, BGC-823/5-FU and SGC-7901/5-FU cells, respectively
Summary
Increasing evidence suggests that aberrant methylation is involved in 5-fluorouracil (5-FU) resistance in gastric cancer (GC). The standard treatment for GC is surgical resection of operable tumors in DNA methylation is a frequent epigenetic event that plays some important role in cancer development. Cancer cells may become drug resistant and escape apoptosis through DNA methylation and other epigenetic modifications. Qin et al Cancer Cell International (2022) 22:86 benefit from 5-FU adjuvant chemotherapy [6], and methylation of PYCARD and DAPK1, the apoptosisrelated genes, resulted in resistance to 5-FU and poor prognoses in GC patients [7]. An increasing number of genes with aberrant methylation, including ASCL2, PCDH17, DCTPP1, TFAP2E, DACT2 and TFAP2E, are found to be related to 5-FU resistance in GC [9,10,11]
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