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Title: Epigenetic silencing of RASSF1A promotes tumourigenesis via alternative transcript expression, SFK activation and exosome secretion
Author: Vlahov, Nikola Vitanov
ISNI:       0000 0004 6352 993X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Loss of the tumour-suppressor gene RASSF1A upon promoter methylation is one of the most frequent events in sporadic human malignancies. Loss of RASSF1A is associated with progression and pathogenesis of solid tumours; and more aggressive clinical phenotype, leading to poor prognosis in breast, lung and colon cancers, amongst others. RASSF1A functions in a number of cellular processes, inducing apoptosis in response to DNA damage, cell cycle arrest and growth control. In tumours with RASSF1 promoter methylation, an alternative isoform, RASSF1C, is expressed and we find is able to bind and activate SRC. We also identify a novel tumour-suppressor role for RASSF1A, associating with the kinase inactivation of SRC. RASSF1C expression promotes SRC-dependent phosphorylation and internalisation of adherens junctions, leading to loss of cell-cell contacts and subsequent increase in cell motility, growth and invasiveness, both in vitro and in vivo. RASSF1C, via active SRC, mediates the phosphorylation of β-catenin and YAP1, promoting their nuclear localisation and association with the transcription factors TEAD1 and TBX3, resulting in the upregulation of anti-apoptotic and pro-survival genes. We show that RASSF1C expression leads to differential packaging and secretion of exosomes, modulating the communication between cancer cells and increasing their tumourigenicity. Finally, we find that cells expressing RASSF1C undergo phenotypic and transcriptional changes associated with the generation of cancer stem cells. We conclude that RASSF1C is an oncogene that plays a variety of roles in cell adhesion, invasion, survival and extracellular communication, resulting in increased tumourigenesis. These functions are inhibited by the tumour suppressor RASSF1A. This work highlights the association of the epigenetic inactivation of the RASSF1A gene with the more aggressive, metastatic tumours, and its relation to increased cancer outcome and risk.
Supervisor: O'Neill, Eric Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available