Abstract 2843: DNMT3B mediated DNA methylation and epigenetic reprogramming of metastatic cancer cells

Abstract

Abstract Approximately 90% of cancer patients die from metastasis. In many cases, current therapies are designed based on the primary tumor characterization and are ineffective against metastatic disease. It is not clear whether metastatic cancer cells acquire additional genetic and epigenetic alterations, if so, what are the underlying mechanisms. Using several tumor models, we demonstrated that DNMT3B, de nova DNA methyltransferase, was increased in metastatic nodules in comparison to that from the primary tumors. DNMT3B knockdown or overexpression significantly inhibited or increased metastatic colonization of cancer cells. To understand the underlying molecular mechanisms of DNMT3B regulation, we performed DNMT3B ChIP-seq, RNA-seq, and DNA methylation-seq comparing lung metastases with primary tumors and 4T1 cells. We identified genes that are differentially methylated and expressed. Ingenuity Pathway Analysis revealed DNMT3B targeting multiple oncogenic signaling pathways. Bioinformatics analysis of human databases demonstrated significantly higher expression levels of DNMT3B in metastases than primary tumors in breast, prostate and melanoma cancer patients. In summary, our study demonstrated that DNMT3B as a key epigenetic regulator which plays critical roles for tumor metastasis. Our work suggests DNMT3B as potential therapeutic targets for breast cancer patients with metastatic disease. Citation Format: Jae Young So, Nicolas Skrypek, Xiang Wang, Anand Merchant, Howard Yang, Wei-Dong Chen, Gangqing Hu, Bhagelu R Achyut, Meggie Cam, Keji Zhao, Maxwell Lee, Li Yang. DNMT3B mediated DNA methylation and epigenetic reprogramming of metastatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2843. doi:10.1158/1538-7445.AM2017-2843