The role of BET attenuation in melanoma
Bromodomain and extra-terminal (BETs) proteins function as epigenetic readers by docking onto acetylated lysine residues (Kac) on histone tails via tandem bromodomains (BRDs), and recruiting protein binding partners via an extra-terminal recruitment domain (ET). Targeting BET BRDs is efficacious in...
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| Бусад зохиолчид: | |
| Формат: | Дипломын ажил |
| Хэл сонгох: | English |
| Хэвлэсэн: |
2020
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| Нөхцлүүд: |
| _version_ | 1826311839626035200 |
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| author | Henderson, EK |
| author2 | Filippakopoulos, P |
| author_facet | Filippakopoulos, P Henderson, EK |
| author_sort | Henderson, EK |
| collection | OXFORD |
| description | Bromodomain and extra-terminal (BETs) proteins function as epigenetic readers by docking onto acetylated lysine residues (Kac) on histone tails via tandem bromodomains (BRDs), and recruiting protein binding partners via an extra-terminal recruitment domain (ET). Targeting BET BRDs is efficacious in different malignancy models; however, the underlying mechanisms remain largely unknown in solid tumours. Together with concerns over toxicity, this calls for a greater understanding of BET protein biology and alternative targeting approaches. p53 influences the phenotype observed in haematopoietic cells following BET BRD inhibition, so it was investigated whether p53 has a similar regulatory role in melanoma. Here, I show that melanoma cells undergo senescence or apoptosis following BET BRD inhibition, and that p53 mutation status potentially correlates with this cell fate decision. Furthermore, BET inhibition up-regulates autophagic flux in melanoma and prostate cancer cells. However, the effect of concomitant autophagy inhibition on cellular proliferation is heterogeneous. Finally, ET domain inhibition leads to autophagy- dependent senescence in melanoma, which provides proof-of-principle that both Kac- dependent and independent targeting of BETs yield a loss of cell viability. |
| first_indexed | 2024-03-07T08:17:13Z |
| format | Thesis |
| id | oxford-uuid:6fa573a5-28fb-49fd-a715-d9e9c06b4f04 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:17:13Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:6fa573a5-28fb-49fd-a715-d9e9c06b4f042024-01-08T09:46:43ZThe role of BET attenuation in melanomaThesishttp://purl.org/coar/resource_type/c_db06uuid:6fa573a5-28fb-49fd-a715-d9e9c06b4f04Melanomap53CancerSkin cancerProstate cancerBET proteinsEnglishHyrax Deposit2020Henderson, EKFilippakopoulos, PGoding, CSavitsky, PBromodomain and extra-terminal (BETs) proteins function as epigenetic readers by docking onto acetylated lysine residues (Kac) on histone tails via tandem bromodomains (BRDs), and recruiting protein binding partners via an extra-terminal recruitment domain (ET). Targeting BET BRDs is efficacious in different malignancy models; however, the underlying mechanisms remain largely unknown in solid tumours. Together with concerns over toxicity, this calls for a greater understanding of BET protein biology and alternative targeting approaches. p53 influences the phenotype observed in haematopoietic cells following BET BRD inhibition, so it was investigated whether p53 has a similar regulatory role in melanoma. Here, I show that melanoma cells undergo senescence or apoptosis following BET BRD inhibition, and that p53 mutation status potentially correlates with this cell fate decision. Furthermore, BET inhibition up-regulates autophagic flux in melanoma and prostate cancer cells. However, the effect of concomitant autophagy inhibition on cellular proliferation is heterogeneous. Finally, ET domain inhibition leads to autophagy- dependent senescence in melanoma, which provides proof-of-principle that both Kac- dependent and independent targeting of BETs yield a loss of cell viability. |
| spellingShingle | Melanoma p53 Cancer Skin cancer Prostate cancer BET proteins Henderson, EK The role of BET attenuation in melanoma |
| title | The role of BET attenuation in melanoma |
| title_full | The role of BET attenuation in melanoma |
| title_fullStr | The role of BET attenuation in melanoma |
| title_full_unstemmed | The role of BET attenuation in melanoma |
| title_short | The role of BET attenuation in melanoma |
| title_sort | role of bet attenuation in melanoma |
| topic | Melanoma p53 Cancer Skin cancer Prostate cancer BET proteins |
| work_keys_str_mv | AT hendersonek theroleofbetattenuationinmelanoma AT hendersonek roleofbetattenuationinmelanoma |