An investigation into YB-1 and its role in tumour progression in medulloblastoma.

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Medulloblastoma is the most frequent malignant childhood brain tumour. Tumours commonlydisseminate; one-third of medulloblastoma cases display metastatic disease at diagnosis and themajority of patients exhibitmetastases at relapse.Whilst long term survival rates amongst averageriskpatients have significantly improved in recent years, outcome for high- and very high-riskpatients with metastatic and recurrent disease remains invariably poorer. Clearly, new treatmentoptions are required to improve survival rates and reduce the life-long cognitive and functionalcomplications associated with current therapies.ATP Binding Cassette (ABC) transporters are highly expressed in numerous cancers, where theyconfer 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 ofchemotherapeutics currently used in medulloblastoma treatment protocols. Y-box binding protein1 (YB-1) represents a potential regulator of the ABCB1 gene. Correlation between YB-1 nuclearexpression and ABCB1 expression has been demonstrated in several cancers and depletion ofYB-1 is associated with reduced activity of the ABCB1 gene. YB-1 is also over-expressed innumerous 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 inmedulloblastoma. In the first year of this project, I have investigated YB-1 expression inmedulloblastoma and found YB-1 to be expressed at both mRNA and protein level in allmedulloblastoma subgroups. For the first time, cellular localisation of YB-1 inmedulloblastoma hasbeen explored and YB-1 and pYB-1(S102) detected in both nuclear and cytoplasmic subcellularcompartments in a range of Group 3, 4 and Sonic Hedgehog (SHH) derived cell lines. Further tothis, treatment with chemotherapeutic and ABCB1 substrate vincristine was found to promotenuclear 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 forfurther research into drug resistance in medulloblastoma.