The epigenetic modifications of histones are versatile marks that are intimately connected to development and disease pathogenesis including human cancers. In this review, we will discuss the many different types of histone modifications and the biological processes with which they are involved. Specifically, we review the enzymatic machineries and modifications that are involved in cancer development and progression, and how to apply currently available small molecule inhibitors for histone modifiers as tool compounds to study the functional significance of histone modifications and their clinical implications.

Summary Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.

MLL3 (also named KMT2C) is a COMPASS subunit that implements H3K4 mono-methylation at gene enhancers. KMT2C frequently incurs point-mutations across a range of human tumors, nevertheless precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within its Plant Homeo Domain (PHD) repeats and demonstrate that this domain mediates association with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated MLL3 PHD mutations disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells bearing MLL3 PHD mutations or lacking BAP1, exhibit reduced enhancer recruitment of MLL3 and the H3K27 demethylase UTX (KDM6A). As the result, inhibiting the H3K27 methyltransferase activity of polycomb repressor complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations, restores normal gene expression patterns and impairs cell proliferation in vivo. This study provides mechanistic insight for the role of MLL3 PHD mutations in cancer and points to restoration of the balanced state of polycomb-COMPASS for the treatment of cancers resulting from mutations in these epigenetic factors.

The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.

An epigenetic axis directs a transcriptional program via enhancer activation by MLL3 COMPASS and TET2-dependent DNA demethylation.