MECP2 promotes migration and invasion of gastric cancer cells via modulating the Notch1/c-Myc/mTOR signaling pathways by suppressing FBXW7 transcription

Abstract

Background: Methyl-CpG-binding protein 2 (MECP2), an epigenetic regulatory factor, promotes the carcinogenesis and progression of a number of cancers. However, its role in the migration and invasion of gastric cancer (GC) as well as the underlying molecular mechanisms remain unclear.Methods: Immunohistochemistry (IHC), Western blot, and quantitative real-time PCR (qRT-PCR) were performed to measure the expressions of MECP2, FBXW7, c-Myc, mTOR and Notch1 in GC tissues and cell lines, respectively. The effects of MECP2 silencing and overexpression on GC cell migration and invasion were detected by wound healing assay and transwell assay. The mechanisms of MECP2-mediated migration and invasion were further investigated using chromatin immunoprecipitation sequencing (ChIP-Seq) and luciferase reporter gene assay.Results: In this study, we found that MECP2 facilitated the migration and invasion of GC cells. Investigation of the molecular mechanism revealed that MECP2 restrained FBXW7 transcription in GC by binding to the methylated CpG sites of FBXW7’s promoter region. MECP2 expression was remarkably negatively correlated with the FBXW7 level in GC tissues. FBXW7 expression was significantly downregulated in GC tissues and cell lines, and low FBXW7 expression was correlated with the clinicopathologic features. FBXW7 repressed cell migration and invasion by regulating the Notch1/c-Myc/mTOR signaling pathways, and knockdown of FBXW7 reversed the effects of silencing MECP2. Moreover, MECP2 upregulated the Notch1/c-Myc/mTOR signaling pathways by inhibiting FBXW7 expression at the transcription level.Conclusion: This study demonstrates that MECP2 promotes migration and invasion of GC cells via modulating the Notch1/c-Myc/mTOR signaling pathways by suppressing FBXW7 transcription. The findings suggest that MECP2 may be a novel effective therapeutic target for GC patients.

Comprehensive Transcriptomic Investigation of Rett Syndrome Reveals Increasing Complexity Trends from Induced Pluripotent Stem Cells to Neurons with Implications for Enriched Pathways

“…In addition, extracellular matrix structures such as perineuronal nets (PNNs), which cover neuronal cell bodies, are more abundant in RTT as compared to healthy brains. , This could be due to disrupted gene expressions of collagens and downregulated COL19A1. The regulatory role of MECP2 on genes involved in processes such as neuronal development, differentiation and signal transduction has been clearly seen. − PNNs of parvalbumin-positive (PV+) cells are particularly effective in neuronal cell differentiation . Differentiation in the OTX2 gene located in the PNNs of PV+ cells could be another factor affecting PNN dysregulation in RTT.…”

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology

“…In another study, researchers found that MeCP2 inhibited FBXW7 expression in GC cells by binding to methylated CpG sites in the FBXW7 promoter, playing important roles in blocking cell migration and invasion. Reduced FBXW7 expression activated the Notch1/c-Myc/mTOR signaling pathways, and promoted GC cells migration and invasion [118].…”

F-box proteins and gastric cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects

“…Methyl-CpG-binding protein 2 (MECP2), an epigenetic regulatory factor, promotes the carcinogenesis and progression of a number of cancers. Zhao et al found that MECP2 could regulate the Notch1/C-MYC/mTOR signaling pathway by inhibiting FBXW7 transcription, thereby promoting GC cell migration and invasion 114 . The catalytically inactive pseudophosphatase serine/threonine/tyrosine interacting protein (STYX) is a member of the protein tyrosine phosphatase family.…”