Hunting for DUBs in cervical and oral cancers

Despite available vaccines, persistent infection with high-risk human papillomavirus (HPV) remains a major global health problem. HPV is the cause of ~5% of the global cancer burden (~630,000 cancers per year), including most cervical carcinomas and an increasing proportion of oropharyngeal and other anogenital cancers.

The Macdonald laboratory uses a range of approaches from global O’Mics screens to biochemical and cell biology analyses to understand how HPV encoded proteins co-opt cellular signalling machinery to dysregulate host gene expression to create an environment that favours virus replication and persistence, predisposing infected cells to transformation. The focus of our work is to identify host factors essential for cancer initiation during HPV infection. This knowledge could underpin new therapeutic strategies to treat virus-induced cancer.

Host cell deubiquitylating enzymes (DUBs) remove ubiquitin from ubiquitylated substrates to regulate their activities and stability. They are a large class of enzymes that play crucial roles in cellular biology, yet are relatively poorly understood in comparison to the enzymes responsible for other forms of post-translational modification, such as phosphorylation. In a recent publication in Oncogene, we showed that the DUB USP13 was activated in cervical cancers and was responsible for mediating an increase in cell growth and survival in those cells. Crucially, loss of USP13 protein or inhibition of its catalytic activity left cervical cancer cells prone to cell death induced by the platinum chemotherapeutic agent cisplatin (Morgan et al., 2021 40(11):2112-2129).

This project will extend these findings to conduct a global analysis of DUBs that play a role in HPV positive cancers of the cervix and oropharynx. Using siRNA technology, we will knock-down expression of all known DUBs and assess the impact on HPV+ cancer cell growth and survival. We will then conduct a biochemical analysis of selected candidate DUBs identified from the screen and using a suite of cancer assays begin to understand their contribution to transformation. We will work closely with clinical colleagues to assess the translational potential of targeting such host factors in therapy.

The Macdonald group instils a positive working environment, where our students and staff work collectively to unravel the machinations of HPV and to identify ways to benefit patients. We espouse equal opportunities and strive to enjoy our time in the lab. Graduate students in the group publish widely and enjoy successes post-graduation in science and beyond. Underlined are references with graduate student authors.

We excel at collaborative research, for this project we will work with Dr Elton Zeqiraj, a biochemist with world-leading expertise in the study of DUBs. As a new independent investigator, Elton shares our ethos around a productive, safe, and workplace.