Stromal cells in the tumour microenvironment play a key role in cancer progression. In human prostate cancer, cancer associated fibroblasts (CAFs) are a major component of the tumour stroma. Prostate CAFs are morphologically and functionally distinct from Non-malignant Prostate Fibroblasts (NPFs), and promote tumour growth and invasion. Identification of the unique epigenetic features of CAFs compared to NPFs would provide important insights into the mechanisms by which CAFs augment tumourigenesis.
We performed genome-wide profiling of four histone modifications (H3K4me1, H3K4me3, H3K27ac and H3K27me3) and RNA-seq in pair-matched CAFs and NPFs from 3 prostate cancer patients. Integration of the histone data allowed accurate mapping of active promoters and enhancers in each cell type, including a subset that were specific to CAFs. We found that many of the CAF-specific active regulatory regions were associated with aberrant gene expression changes. These included genes involved in extracellular matrix remodeling and angiogenesis, which are essential for tumour malignancy and metastatic progression.
This work presents the first genome-wide profile of histone modifications in stromal cells of any tumour type to date. Initial results pinpoint consistent epigenetic differences between NPFs and CAFs that may regulate the expression of genes implicated in tumour progression. Our results will provide an increased understanding of the molecular underpinnings of cancer progression.