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Investigating the interplay between c-Myc and HSF1 in early oncogenesis

Jones, Joe; (2021) Investigating the interplay between c-Myc and HSF1 in early oncogenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancers must deregulate many cellular processes in order to promote growth and survival. As a consequence, this dysregulation causes a rise in oncogenesis-related stresses that cancer cells must tolerate through upregulation of stress support pathways. Genotoxic stress, any event that increases genomic instability, and proteotoxic stress, the perturbation of proteostasis, are amongst the most common stress phenotypes of cancer. The transcription factor HSF1 coordinates a transcriptional response to proteotoxic stress, upregulating protein chaperones that guide correct protein folding and disassemble protein aggregates. Interestingly, HSF1 appears to be important for oncogenesis, with an upregulation of HSF1 observed in many cancers. However, many questions remain about how this upregulation occurs and why HSF1 is needed for cancer cell survival. In this project, I focus on the interplay between the oncogene c-Myc and HSF1. I show that HSF1 is upregulated upon c-Myc activation, both as a consequence of an increase in proteotoxic stress but also through a direct transcriptional effect. Following this, I show an important role for HSF1 in increasing the tolerance to c-Myc-induced DNA damage and replication stress. My work suggests that much of the genotoxic stress generated by c-Myc activation is the result of an increase in proteotoxic stress. This interplay between c-Myc and HSF1 is exemplified by a dependence on HSF1 for survival in c-Myc activated cells, demonstrating the importance of HSF1 in supporting the oncogenic activities of c-Myc. This work has interesting implications for the development of cancer therapeutics, as exploiting the reliance on HSF1 in c-Myc-driven cancers will lead to more selective treatments.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating the interplay between c-Myc and HSF1 in early oncogenesis
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10124470
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