Histones and their modifications in ovarian cancer - drivers of disease and therapeutic targets

Abstract

Epithelial ovarian cancer has the highest mortality of the gynecological malignancies. High grade serous epithelial ovarian cancer (SEOC) is the most common subtype, with the majority of women presenting with advanced disease where 5-year survival is around 25%. Platinum-based chemotherapy in combination with paclitaxel remains the most effective treatment despite platinum therapies being introduced almost 40 years ago. Advances in molecular medicine are underpinning new strategies for the treatment of cancer. Major advances have been made by international initiatives to sequence cancer genomes. For SEOC, with the exception of TP53 that is mutated in virtually 100% of these tumors, there is no other gene mutated at high frequency. There is extensive copy number variation, as well as changes in methylation patterns that will influence gene expression. To date, the role of histones and their post-translational modifications in ovarian cancer is a relatively understudied field. Post-translational histone modifications play major roles in gene expression as they direct the configuration of chromatin and so access by transcription factors. Histone modifications include methylation, acetylation, and monoubiquitination, with involvement of enzymes including histone methyltransferases, histone acetyltransferases/deacetylases, and ubiquitin ligases/deubiquitinases, respectively. Complexes such as the Polycomb repressive complex also play roles in the control of histone modifications and more recently roles for long non-coding RNA and microRNAs are emerging. Epigenomic-based therapies targeting histone modifications are being developed and offer new approaches for the treatment of ovarian cancer. Here, we discuss histone modifications and their aberrant regulation in malignancy and specifically in ovarian cancer. We review current and upcoming histone-based therapies that have the potential to inform and improve treatment strategies for women with ovarian cancer.

Keywords: deubiquitinases; histone; histone deacetylase inhibitors; histone methyltransferases; lncRNA; ovarian cancer; polycomb repressive complex; splicing.

Figure 1

Postulated patterns of histone cross-talk in malignancy. (A) Lysine 120 of histone H2B is acetylated by histone acetyltransferases (HATs), acting as a precursor for histone H2B monoubiquitination at the same amino acid residue. (B) Lysine 120 of histone H2B becomes deacetylated via histone deacetylases (HDACs), allowing for the E3 ubiquitin ligase complex of RNF20/RN40, in association with the PAF1 transcriptional regulatory complex (PAFC) to facilitate monoubiquitination of lysine 120 (H2Bub1). (C) SET1 is recruited to the site of H2Bub1 where it interacts with COMPASS (complex of proteins associated with Set1) to facilitate the active mark of methylated histone 3 at lysine 4 (H3K4me). (D) H2Bub1 can recruit and activate the DOT1L methyltransferase, responsible for the active chromatin mark of methylated histone H3 at lysine 79 (H3K79me).

Figure 2

HOTAIR-directed epigenetic reprograming of the cancer genome. (A) The long intergenic non-coding (linc) RNA HOTAIR recognizes specific DNA sequences and targets chromatin-modifying complexes PRC2 and LSD1 to silence gene loci. The 5′ end of HOTAIR tethers the PRC2 complex to the target by binding to the non-coding RNA binding domain (ncRBD) of the HMTase EZH2, catalyzing tri-methylation of H3K27. The 3′ end of HOTAIR facilitates demethylation of H3K4me2 by the lysine-specific demethylase LSD1. Both H3K27me3 and lack of methylation at H3K4 are repressive chromatin marks associated with gene silencing. (B) Expression of HOTAIR results in silencing of >40-kb region spanning HOXD8–11 of the HOXD locus. Aberrant HOTAIR expression in multiple cancers has been shown to promote invasiveness.

Figure 3

Current and upcoming therapies for the targeting of epigenetic modifiers in ovarian cancer. Tumor suppressor genes are commonly silenced in ovarian cancer through epigenetic writers and erasers (blue ovals). These proteins regulate a variety of modifications including DNA methylation (DNMTs), histone methylation (EZH2), the removal of both histone acetylation (HDACs), and histone monoubiquitination (DUBs). Various inhibiting agents (red ovals) have been designed to stop the action of these enzymes. DNA methyltransferases (DNMTs) silence tumor suppressor genes (red line) by hypermethylation of CpG islands in gene promoters (yellow line). Consequently, DNMT inhibitors (DNMTi) are currently being trialed in ovarian cancer cell models with value in the reactivation of a tumor suppressive phenotype. Deubiquitinating enzymes (DUBs) function to cleave ubiquitin from their target proteins. Recent research has demonstrated H2Bub1 is lost in ovarian cancer, implicating H2Bub1-specific DUBs. H2Bub1-associated DUB inhibitors (DUBi) may be viable treatments for ovarian cancer. The histone methyltransferase EZH2 is a member of the Polycomb repressive complex 2 (PRC2). EZH2 functions to tri-methylate lysine 27 of histone H3 (H3K27), a repressive chromatin mark. Consequently, EZH2-inhibitors (EZH2i) are currently being trialed to remove this repressive mark. Histone deacetylase (HDACs) remove acetyl groups from specific histone residues. HDAC inhibitors (HDACi) prevent this enzymatic function, facilitating gene transcription.