The 8p11-p12 amplicon oncogene ASH2L regulates expression of genes involved in tumorigenic processes via promoter H3K4me3 in luminal breast cancer.

Amplification of the 8p11-p12 genomic region occurs in 30% of luminal B breast cancers and results in coordinate overexpression of several oncogenes, including ASH2L, which upregulates gene expression via promoter tri-methylation of lysine 4 on histone 3 (H3K4me3). Since 8p11-p12 amplification is associated with endocrine resistance, the major cause of breast cancer mortality, understanding the underlying biology is essential to improving treatment options for patients. To explore the role of amplified and overexpressed ASH2L on epigenetic regulation of gene expression, we performed H3K4me3 ChIP-seq and RNA-seq in breast cancer cells with ASH2L amplification and overexpression following ASH2L knockdown and assessed the biological effects of the suite of genes identified in this manner. We discovered that ASH2L-regulated genes are implicated in cell cycle processes and response to the CDK4/6 inhibitor palbociclib and confirmed these effects in additional breast cancer cell lines. We also discovered that ASH2L regulates expression of another 8p11-p12 amplicon oncogene NSD3, also an epigenome modifier, which has previously been shown to result in overexpression and estrogen-independent activation of ERα. Together, these data establish ASH2L as a breast cancer oncogene and an important component of the 8p11-p12 amplicon that acts as an oncogenic unit in breast cancer.