Transcriptional reprogramming regulated by DNMT3B - histone modification interaction in breast cancer metastasis

Authors

• X Wang
• JY So
• JD Fan
• KJ Zhao
• L Yang

Abstract

Tumor metastasis is the leading cause of cancer mortality. It is a multi-step process which includes local tumor cell invasion into the surrounding tissue, entry into the vasculature followed by the exit of carcinoma cells from the circulation and colonization at the distant sites. Current cancer treatment strategy is largely based on the genetic characterization of primary tumors and is ineffective for metastatic disease. Consistently, very few genetic mutations have been identified as drivers of metastasis. We hypothesize that epigenetic and transcriptional mechanisms are critical which could be influenced by the tumor microenvironment. We found that DNMT3B, a de novo methyltransferase promotes metastasis of breast cancer cells by regulating the gene expression of several pathways. How DNMT3B specific regulates these genes during metastasis remains unknown. Previous studies indicate the histone binding motifs in DNMT3B is critical for the its genomic localization. Using histone modification peptide array and ELISA assay, we found that DNMT3B specific associated with several histone modifications in the progress of metastasis. These interactions were validated in vivo by the ChIP and proximity ligation assay. Notably, we first observed that DNMT3B regulated the metastasis-associated genes through interacting with histone modifications. Our findings reveal how histone modification guides the de novo methyltransferase activity, which is critical for transcriptional reprogramming of metastatic cancer cells. Our studies provide insights for mechanistic understanding and therapeutic options for breast cancer metastasis.

Scientific Focus Area: Chromosome Biology

This page was last updated on Friday, March 26, 2021