Genome-wide Epigenetic Profiling Reveals The Histone Methylation Dynamics In Breast Tumor Transformation

Cancer is one of the most dangerous diseases to human health. The early diagnosis and treatment have been proved to be the best way to prevent and treat cancers. However, effective molecular markers and drug targets are still required to be identified. Recent reports reveal that epigenetic alterations are as important as genetic mutations in tumor cell transformation. To understand the epigenetic mechanisms during tumor cell transformation will provide important clues for clinical studies. Here we developed an in vitro primary cell-derived breast cancer transformation model. We found histone H3K9me2 and me3 decrease in the model and in vivo clinical breast cancer tissues. ChIP-Seq analysis showed that H3K9me3 small peaks are enriched with transcription factors and change dramatically during transformation but not large regions. H3K9me3 decrease causes the instability of chromatin, which enhances DNA damage. H3K9me2 reduction alters transcriptional programs and the boundaries of decreased H3K9me2 LOCKs are enriched with cancer-related genes. Furthermore, we identified KDM3A, a demethylase for H3K9 me 1/2, increases during the transformation and in cancer tissues. KDM3A deficiency impairs the growth of transformed cell lines and its overexpression promotes tumor formation. KDM3A regulates H3K9me2 and expression level in some cancer-related genes. Taken together, we studied the dynamic epigenome during cancer cell transformation, and identified KDM3A as an oncogene, reveal key epigenetic markers and mechanisms of the process, and provide novel molecular candidates for early diagnosis and drug design in breast cancer treatment.