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Updated: May 8, 2026

Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Annexin A6 is down-regulated through promoter methylation in gastric cancer
Xian Wang1, Shengjie Zhang, Jianbin Zhang
1Department of Medical Oncology, Laboratory of Cancer Biology, Institute of Clinical Science, Sir Runrun Shaw Hospital, Medical School of Zhejiang University Hangzhou, China.
Background:
The aberrant activation of oncogenic signaling such as Ras/MAPK signaling is a frequent event in human cancers. In addition to genetic changes, epigenetic silencing of inhibitors in Ras/MAPK signaling contributes to the activation of Ras/MAPK signaling. Recently, ANXA6 has been shown to interact with Ras-GAP1 and inhibit Ras activation in human breast cancer. However, whether and how it is involved in human cancers remain unknown.
Methods:
Real-time PCR was used to determine ANXA6 expression in gastric cancer cells and primary gastric carcinomas. Next, we explored the methylation of ANXA6 promoter in cell lines and tumor tissues with methylation-specific PCR and bisulfite genomic sequencing. We also investigated the function of ANXA6 in gastric cancer cells with colony formation assay and western blotting analysis.
Results:
ANXA6 was down-regulated in gastric cancer cells and primary gastric carcinomas. Ectopic ANXA6 expression inhibited the growth of gastric cancer cells and the activity of Ras/MAPK signaling. Its expression was restored after pharmaceutical demethylation. ANXA6 promoter was methylated in gastric cancer cell lines (6/6) and primary gastric carcinoma tissues (29/156). Interestingly, the knockdown of oncoprotein Yin Yang 1 (YY1) also restored ANXA6 expression and promoted the demethylation of ANXA6 promoter. However, ANXA6 methylation was not associated with clinical parameters such as differentiation, and TNM staging. Neither Kaplan-Meier Curve nor Cox regression analysis revealed a significant role of ANXA methylation to predict the survival of gastric cancer patients.
Conclusions:
We firstly reported that ANXA6 is epigenetically silenced through promoter methylation in human cancers and YY1 is important to initiate or maintain ANXA6 promoter methylation in gastric cancer cells. ANXA6 functions as a tumor suppressor in gastric cancer cells through the inhibition of Ras/MAPK signaling. ANXA6 methylation is not a prognostic factor for gastric cancer patients.
Insights
Annexin A6 (ANXA6) acts as a tumor suppressor in gastric cancer by inhibiting Ras/MAPK signaling. Its silencing via promoter methylation, influenced by YY1, is a key event in cancer development but not a prognostic indicator.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Aberrant Ras/MAPK signaling is common in human cancers.
- Epigenetic silencing of pathway inhibitors contributes to Ras/MAPK activation.
- ANXA6's role in Ras inhibition in breast cancer suggests broader involvement in human cancers.
Purpose of the Study:
- To investigate the role of ANXA6 in gastric cancer.
- To determine if ANXA6 is epigenetically silenced in gastric cancer.
- To explore the mechanism of ANXA6 silencing and its functional impact.
Main Methods:
- Real-time PCR for ANXA6 expression analysis.
- Methylation-specific PCR and bisulfite sequencing for promoter methylation.
- Colony formation assays and western blotting for functional studies.
Main Results:
- ANXA6 is downregulated in gastric cancer due to promoter methylation.
- ANXA6 re-expression inhibits gastric cancer cell growth and Ras/MAPK activity.
- Yin Yang 1 (YY1) promotes ANXA6 promoter methylation.
- ANXA6 methylation is not associated with clinical parameters or patient survival.
Conclusions:
- ANXA6 is epigenetically silenced by promoter methylation in gastric cancer, with YY1 involvement.
- ANXA6 functions as a tumor suppressor by inhibiting Ras/MAPK signaling.
- ANXA6 methylation status does not predict prognosis in gastric cancer patients.
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