About the Project
Abnormal cellular signalling is a hallmark of cancer, and the target of many drugs used to treat cancer. Our research focuses on the deubiquitylases (DUBs), a family of enzymes that remove ubiquitin, a molecular tag that has far-reaching impacts on protein stability, function and localisation. DUBs contribute to multiple cancer signalling pathways (1) and are potentially druggable targets. Using siRNA library screening we match DUBs with cancer-associated proteins, to determine novel roles in signalling and transcription (2, 3). Here we will investigate Hippo signalling. This highly conserved pathway is often dysregulated in cancer (4), adversely affecting survival of patients, including those with head-and-neck squamous carcinoma (HNSC) and mesothelioma (MPM), two cancers of elevated incidence in Merseyside. The Hippo kinases, MST1/2 and LATS1/2, normally prevent YAP/TAZ co-activators shuttling into the nucleus, where they would activate TEAD transcription factors to drive proliferation (4). In most solid tumours however, YAP/TAZ are aberrantly activated and are essential for cancer initiation/growth. Key roles for DUBs in Hippo-signalling have started to emerge (5), e.g. screens using affinity-mass spectrometry showed that USP9X regulates LATS1/2 (6). Through our collaboration, we have begun to identify new candidate DUBs that regulate expression of Hippo pathway components using DUB siRNA screens. This project will screen for oncogenic DUBs that regulate activity of YAP/TAZ and the TEADs; such DUBs present exciting new therapeutic targets.
To elucidate novel mechanisms by which DUBs interplay with YAP/TAZ/TEAD activation that may be translated for benefit in HNSC/MPM cancers, by:
1. Performing DUB siRNA screens in cancer cells to identify and characterise DUBs that promote YAP/TAZ/TEAD activation.
2. Establishing mechanisms of action for key DUBs in YAP/TAZ/TEAD activation.
3. Assessing expression of key DUBs in cancer samples, as potential surrogate biomarkers of dysregulated Hippo-signalling or new therapeutic targets.
The student will acquire skills in a broad range of molecular biology, cell biology, and molecular pathology techniques. They will divide their time between the Institute of Systems, Molecular and Integrative Biology (ISMIB, University of Liverpool, UK) supervised by Prof Coulson and Dr Sacco, and the Institute of Molecular and Cell Biology (IMCB, A*STAR, Singapore) supervised by Dr Chan and Prof Wong.
IMCB (www.imcb.a-star.edu.sg/) is an autonomous research institute of the Agency for Science, Technology and Research (A*STAR). Over 30 years IMCB has fostered a vibrant research culture, enabling cutting edge discoveries and nurturing high-quality talent, to transform Singapore into an international hub for biomedical research. IMCB has trained more than 250 PhD students, recruited more than 800 PhDs from the international community, and published over 2,500 research papers in top international journals. IMCB has collaborations with industrial, translational, clinical and academic partners worldwide. Their vision is to remain a premier molecular biology and cell institute with increasing focus on the mechanistic basis of human diseases: cancer cell signaling being one of their 5 major programs in discovery research.
ISMIB integrates research into the biology of life across a magnitude of scales, from single molecules through to whole organisms and uses cutting-edge multi-omics technologies to answer impactful biological questions. In our department
(https://www.liverpool.ac.uk/translational-medicine/departmentsandgroups/cellular-and-molecular-physiology/about/) research groups, working across discovery and translational sciences, investigate how cellular communication systems control the behaviour of cells, tissues and organisms. The results of our research help inform new therapeutic strategies. Our major research themes focus on gene regulatory and cell signalling networks underpinning normal cell biology and diseases such as cancer.
The studentship will commence after 1st January 2021. Applicants will have a first class or upper second-class honours degree (or equivalent) in the biological sciences, and may have additional masters level research experience in cell biology, biochemistry or cancer research. Formal applications, including a cover letter outlining your reasons for applying and a curriculum vitae with the names and contact details of at least two academic referees who can comment on your research skills, should be submitted via email to Mrs Debbie Horne, [email protected].
The University of Liverpool is fully committed to promoting equality and ISMIB holds an Athena SWAN Gold Award.
Informal enquiries: Prof Judy Coulson, [email protected]
Formal applications: Mrs Debbie Horne, [email protected]
2. Faronato, et al., Coulson. (2013) The deubiquitylase USP15 stabilizes newly synthesised REST and rescues its expression at mitotic exit. Cell Cycle 12(12):1964-77.
3. Sacco, et al., Coulson. (2014) The deubiquitylase Ataxin-3 restricts PTEN in lung cancer cells. Oncogene 33(33):4265-4272.
4. Chan, et al., Hong. (2011) The Hippo pathway in biological control and cancer development. J Cell Physiol. 226(4):928-939.
5. Mussell et al. (2019)Regulation of Hippo signaling by deubiquitinating enzymes in cancer. Genes&Diseases 6:335-341.
6. Toloczko, et al. Hong, Chan. (2017). DUB USP9X suppresses tumor growth... Cancer Res 77:4921-4933.
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