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.

An overview of long non-coding RNAs in ovarian cancers

“…The first study by Qiu et.al [74] included ovarian carcinoma patients with serous subtype, whereas the second study by Teschendorff et.al [75] included all subtypes (serous, mucinous, endometrioid, clear cell) as well as fallopian tube and non-classifiable tumors, which could possibly explain this discrepancy. In the A2780cisR cell line, a cisplatin-resistant counterpart of A2780, HOTAIR was expressed 5-fold higher and its downregulation recapitulated cisplatin sensitivity [76]. Similarly, HOTAIR expression led to resistance to cisplatin in several ovarian cancer cell lines through activation of the Wnt/β-catenin pathway [77].…”

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

“…However, in a phase II study, vorinostat displayed minimal activity as a single agent for treating persistent or recurrent epithelial ovarian or primary peritoneal carcinoma, despite its acceptable tolerability 121. A phase II trial examining the use of romidepsin for the treatment of ovarian cancer is ongoing 122. Valproate exhibits direct HDACI activity, although the associated mechanisms of action remain unclear.…”

Drug Resistance in Bacteria, Fungi, Malaria, and Cancer

“…The proteins that add, remove, or interpret these modifications on histones are thus called as chromatin "writers", "erasers" or "readers" respectively (Marsh et al 2014). While HATs help in opening up the chromatin by acetylation and thus induce gene expression, the HDACs on the opposite hand help making it inaccessible for transcription by deacetylating the histones.…”