An investigation into YB-1 and its role in tumour progression in medulloblastoma.
Lead Research Organisation:
University of Nottingham
Department Name: School of Medicine
Abstract
Medulloblastoma is the most frequent malignant childhood brain tumour. Tumours commonly
disseminate; one-third of medulloblastoma cases display metastatic disease at diagnosis and the
majority of patients exhibitmetastases at relapse.Whilst long term survival rates amongst averagerisk
patients have significantly improved in recent years, outcome for high- and very high-risk
patients with metastatic and recurrent disease remains invariably poorer. Clearly, new treatment
options are required to improve survival rates and reduce the life-long cognitive and functional
complications associated with current therapies.
ATP Binding Cassette (ABC) transporters are highly expressed in numerous cancers, where they
confer multi-drug resistance in malignant cells. ATP binding cassette subfamily B member 1
(ABCB1) expression correlates with high-risk medulloblastoma and is known to efflux a number of
chemotherapeutics currently used in medulloblastoma treatment protocols. Y-box binding protein
1 (YB-1) represents a potential regulator of the ABCB1 gene. Correlation between YB-1 nuclear
expression and ABCB1 expression has been demonstrated in several cancers and depletion of
YB-1 is associated with reduced activity of the ABCB1 gene. YB-1 is also over-expressed in
numerous cancers, with elevated nuclear expression frequently associated with poor prognosis.
Although well researched in other cancers, very little is known about the role of YB-1 in
medulloblastoma. In the first year of this project, I have investigated YB-1 expression in
medulloblastoma and found YB-1 to be expressed at both mRNA and protein level in all
medulloblastoma subgroups. For the first time, cellular localisation of YB-1 inmedulloblastoma has
been explored and YB-1 and pYB-1(S102) detected in both nuclear and cytoplasmic subcellular
compartments in a range of Group 3, 4 and Sonic Hedgehog (SHH) derived cell lines. Further to
this, treatment with chemotherapeutic and ABCB1 substrate vincristine was found to promote
nuclear localisation of YB-1 in SHH cell line DAOY. Finally, utilising chromatin immunoprecipitation
(ChIP) analysis, we have shown that YB-1 binds to an inverted CCAAT box in the ABCB1 promoter,
suggesting that YB-1 may represent a novel regulator of the ABCB1 gene in medulloblastoma.
Although further experiments are required, these findings identify YB-1 as a compelling target for
further research into drug resistance in medulloblastoma.
disseminate; one-third of medulloblastoma cases display metastatic disease at diagnosis and the
majority of patients exhibitmetastases at relapse.Whilst long term survival rates amongst averagerisk
patients have significantly improved in recent years, outcome for high- and very high-risk
patients with metastatic and recurrent disease remains invariably poorer. Clearly, new treatment
options are required to improve survival rates and reduce the life-long cognitive and functional
complications associated with current therapies.
ATP Binding Cassette (ABC) transporters are highly expressed in numerous cancers, where they
confer multi-drug resistance in malignant cells. ATP binding cassette subfamily B member 1
(ABCB1) expression correlates with high-risk medulloblastoma and is known to efflux a number of
chemotherapeutics currently used in medulloblastoma treatment protocols. Y-box binding protein
1 (YB-1) represents a potential regulator of the ABCB1 gene. Correlation between YB-1 nuclear
expression and ABCB1 expression has been demonstrated in several cancers and depletion of
YB-1 is associated with reduced activity of the ABCB1 gene. YB-1 is also over-expressed in
numerous cancers, with elevated nuclear expression frequently associated with poor prognosis.
Although well researched in other cancers, very little is known about the role of YB-1 in
medulloblastoma. In the first year of this project, I have investigated YB-1 expression in
medulloblastoma and found YB-1 to be expressed at both mRNA and protein level in all
medulloblastoma subgroups. For the first time, cellular localisation of YB-1 inmedulloblastoma has
been explored and YB-1 and pYB-1(S102) detected in both nuclear and cytoplasmic subcellular
compartments in a range of Group 3, 4 and Sonic Hedgehog (SHH) derived cell lines. Further to
this, treatment with chemotherapeutic and ABCB1 substrate vincristine was found to promote
nuclear localisation of YB-1 in SHH cell line DAOY. Finally, utilising chromatin immunoprecipitation
(ChIP) analysis, we have shown that YB-1 binds to an inverted CCAAT box in the ABCB1 promoter,
suggesting that YB-1 may represent a novel regulator of the ABCB1 gene in medulloblastoma.
Although further experiments are required, these findings identify YB-1 as a compelling target for
further research into drug resistance in medulloblastoma.
Organisations
People |
ORCID iD |
| Elizabeth Coyle (Primary Supervisor) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M008770/1 | 01/10/2015 | 31/03/2024 | |||
| 1945010 | Studentship | BB/M008770/1 | 01/10/2017 | 30/09/2021 |
| Description | Medulloblastoma represents the most frequent, aggressive brain cancer in children. It can be classified into four main types and our research is focused on the type that carries the worst prognosis. Unfortunately, tumours of this type frequently develop resistance to drug treatment, a factor which significantly hinders the success of chemotherapy. Accordingly, 5-year survival for this aggressive tumour type lies at just 50%. It is clear that a deeper understanding of medulloblastoma resistance is required to improve therapy efficacy and hence survival rates for such patients. Recently, we have identified a protein called Y-box binding protein (YB-1) to be highly expressed in medulloblastoma and shown that high expression correlates with poor overall survival. YB-1 is a regulatory protein which by moving into cell's nucleus (control centre) can regulate the amount of other proteins within the cell. In other cancers, the presence of YB-1 in the nucleus has been associated with poor prognosis and drug resistance. Intriguingly, we have shown that treatment of medulloblastoma cells with chemotherapy drugs, which are currently used in medulloblastoma treatment protocols, causes YB-1 to move to the nucleus. We have also discovered that, in the nucleus, YB-1 may directly regulate the expression of a transport protein that can export some chemotherapy drugs out of cancer cells. Together, our exciting data indicates that YB-1 may represent a novel regulator of drug resistance and disease progression in medulloblastoma. |
| Exploitation Route | We have recently been awarded funding to undertake a large ChIP-Sequencing project. In doing this, we hope to identify novel YB-1 targets implicated in chemoresistance in medulloblastoma. This data will shape future studies which will focus on testing different compounds to inhibit such targets with the aim to develop novel combined therapy approaches that may overcome resistance in medulloblastoma. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Stoneygate Proof of Concept Award |
| Amount | £35,568 (GBP) |
| Organisation | University of Nottingham |
| Department | Children’s Brain Tumour Research Centre |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 03/2020 |
| End | 03/2021 |
| Description | School Talk (Nottingham) for International Women in Science Day |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | I gave a talk about my research and being a women in science for International Women and Girls in Science Day at St Teresa's Primary School in Nottingham. The students asked lots of very in depth questions which confirmed their engagement in the talk. |
| Year(s) Of Engagement Activity | 2020 |