Abstract 105: An epigenetic vicious cycle of DNMT, protein Tyrosine phosphatase receptor type R, and the MAPK pathway in cancer metastasis

Abstract

Abstract Introduction: Epigenetic modifications are a driving force in carcinogenesis. In addition to its role in initiation and promotion, DNA methylation is thought to participate in cancer metastasis. The present study is to interrogate the role of de novo DNA methylation in cervical cancer invasions. Methods and Results: Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and that DNMT3B interference inhibits metastasis. Using methyl-DNA immunoprecipitation coupled with microarray analysis (mDIP-on-chip), we found that Protein Tyrosine Phosphatase Receptor Type R (PTPRR) is targeted by DNMT3B. PTPRR inhibited metastasis by inhibiting p44/42 MAPK signaling, epithelial-mesenchymal transition (EMT), and matrix metalloproteinase 9 (MMP9) expression. PTPRR also inhibited the expression of transcription factor AP1, HPV oncogenes, and DNMTs, and reciprocally demethylated the PTPRR promoter. The methylation status of PTPRR was increased in cervical scrapings in accordance with disease severities, and immunohistochemical staining confirmed that PTPRR protein was expressed in precancerous lesions but was silenced in invasive cancers. The clinical correlation results suggest that methylation of the PTPRR promoter is a potential biomarker for cervical cancer detection. Conclusion: This study demonstrates for the first time that DNMT3B plays an important role in the cervical cancer invasion and metastasis. The DNMT3B-mediated silencing of PTPRR activates p44/42 MAPK signaling and its multiple downstream effectors such as EMT, enabling the in situ tumors becoming invasive. MAPK signaling also augments the expression of DNMTs, which further consolidates the methylation silencing of PTPRR. A vicious cycle between epigenetic machinery and oncogenic signaling promotes cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 105. doi:10.1158/1538-7445.AM2011-105