DUBs in uveal melanoma - version 1
Research type
Research Study
Full title
DUB family members and DUB-regulated protein expression in Uveal Melanoma
IRAS ID
264893
Contact name
Sarah, E Coupland
Contact email
Duration of Study in the UK
4 years, 2 months, 30 days
Research summary
Research Summary
Uveal melanoma (UM) is a rare eye cancer occurring in adults. In around 50% of patients the cancer will spread from the eye to distant sites, in particular the liver, and there are currently no effective treatments once this has happened. If we are to improve the survival rate for patients with UM, it is essential that we develop a better understanding of the disease mechanisms.
A number of cell processes are often disrupted in cancer. Several of these processes involve factors called DUBs that control the turnover of important molecules within cells. When this turnover is not working properly this can lead to increased proliferation of the cancer cells. Drugs that target DUBs are currently being developed with the aim that this will lead to increased success in the treatment of various cancers. The aim of this study therefore is to examine whether DUBS are detected in UM cells and to determine their relationship with UM cell behaviour and patient outcome.Summary of results
Uveal melanoma (UM) is a rare eye cancer that spreads to the liver in around a half of all diagnosed patients. When the cancer cells from the eye grow in the liver, they are generally fatal due to a lack of successful therapies. In 80% of the cases where the eye cancer spreads to the liver, the patients have a genetic change in a gene called BAP1. These changes result in the inactivation and absence of the BAP1 protein in the tumour cells. We believe reprogramming of the cancer cells occurs when BAP1 is altered leading to vulnerabilities and potential new therapeutic targets. BAP1 is a factor known as a deubiquitinase (DUB). DUBs can edit processes that occur in cells and are often altered in cancer. This study mapped DUBs to the regulation of specific cancer-associated proteins to understand the resulting cancer phenotypes and identify potential therapeutic targets. The outcomes of the study were:
1. During cell division the machinery that regulates this is often altered in cancer cells. This process relies on the kinesin KIFC1, which can be regulated by the attachment of small ubiquitin molecules that lead to its degradation. DUBs can remove ubiquitin from protein targets and rescue them from degradation. In our studies, KIFC1 was shown to be involved in the division of UM cells with an absence of this factor leading to aberrant cell division and ultimately cell death.
2. Analysis of multiple datasets from BAP1-normal and BAP1-altered cells identified markers that may be regulated by this factor. The identified 4 markers were then analysed in UM tissue to validate their association with BAP1 and potential clinical significance. Two of these, KCND3 and FSCN1 showed potential as therapeutic targets for this disease.REC name
West of Scotland REC 3
REC reference
19/WS/0104
Date of REC Opinion
4 Jul 2019
REC opinion
Favourable Opinion