Emerging roles of the cancerous inhibitor of protein phosphatase 2A (CIP2A) in ovarian cancer

Abstract

Ovarian cancer (OvCa) is the sixth most common gynaecological cancer in the UK, accounting for over 200,000 deaths worldwide. Cancerous Inhibitor of Phosphatase 2 A (CIP2A) is an oncoprotein and an endogenous inhibitor of PP2A. CIP2A is a key regulator for cellular processes (e.g. proliferation, DNA damage) and is involved in the progression of many malignancies. In this study we provide a comprehensive overview of its role in OvCa making use of in silico tools, clinical samples and in vitro models. CIP2A is overexpressed in OvCa patients, with metastatic patients having significantly higher expression when compared to patients with malignant and benign ovarian tumours. High CIP2A expression reduces both overall-and progression-free survival, whereas an R530T mutation is predicted to cause structural destabilisation of the CIP2A dimer. We also provide evidence for microRNA (miRNA) and mRNA target interactions with CIP2A. Finally, we have studied the effects of CIP2A inhibition in an in vitro BRCA2 model compared to BRCA2 wild-type OvCa cells, using RNA-sequencing. Gene enrichment pointed towards changes p53 pathway, protein metabolism, transporter activity, DNA replication, and cell cycle. Our data provide a novel insight into the role of CIP2A in OvCa and the potential of drug repurposing for therapeutic interventions.