dc.contributor.advisor | Hahn, William C | |
dc.contributor.author | Lee, Sun Joo | |
dc.date.accessioned | 2024-03-13T04:11:20Z | |
dc.date.created | 2024 | |
dc.date.issued | 2023-12-12 | |
dc.date.submitted | 2024-03 | |
dc.identifier.citation | Lee, Sun Joo. 2023. Systematic Interrogation of CBP/p300 Dependency in Cancer. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences. | |
dc.identifier.other | 30816298 | |
dc.identifier.uri | https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37377859 | * |
dc.description.abstract | CBP and p300 are closely related paralogs that function as versatile transcriptional co-activator proteins. These paralogs function as histone acetyltransferases (HATs) and mediate canonical signaling programs by acetylating histone H3 lysines 18 and 27 (H3K18ac; H3K27ac) at regulatory elements such as promoters and enhancers. These genomic loci play critical roles in the context of cancer and are essential to maintain oncogenic transcription. Therefore, the p300/CBP HATs are attractive targets for disrupting epigenetically regulated oncogenic transcription programs. Several inhibitors of p300/CBP HATs have been reported, with A-485 being one of the best-characterized. A-485 has been shown to selectively inhibit cell proliferation across lineage-specific tumor types, suggesting the potential of therapeutically targeting p300 and CBP in cancer. However, the landscape of sensitivities to p300/CBP inhibition or deletion in cancer remain unknown, and a clear biomarker of p300/CBP dependency is lacking. To address this, we systematically functionalized the impact of p300 and CBP knock-out individually and in combination across hundreds of human cancer cell models (PRISM) to unbiasedly identify oncogenic contexts that confer p300/CBP dependency. We have identified a subset of 37 cell lines genetically dependent on the double knockout of p300/CBP (log2fc 2 std). We found that the dependent cell lines were not enriched in a particular lineage and had no associated biomarker. Additionally, complementary inhibitor (A-485) screens identified a lack of correlation between p300/CBP genetic dependency and inhibitor sensitivity. Finally, we report p300 and CBP are selectively required for the expression of JUN, a proto-oncogene part of the AP-1 transcription factor complex, in the p300/CBP dependent cell lines but not in the non-dependent lines. This suggests a potential mechanism where p300/CBP dependent cancer cell lines are vulnerable to p300/CBP loss through the loss of c-Jun. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dash.license | LAA | |
dc.subject | Cancer | |
dc.subject | CBP | |
dc.subject | Epigenetics | |
dc.subject | high throughput screen | |
dc.subject | oncogene | |
dc.subject | p300 | |
dc.subject | Oncology | |
dc.subject | Biology | |
dc.title | Systematic Interrogation of CBP/p300 Dependency in Cancer | |
dc.type | Thesis or Dissertation | |
dash.depositing.author | Lee, Sun Joo | |
dc.date.available | 2024-03-13T04:11:20Z | |
thesis.degree.date | 2023 | |
thesis.degree.grantor | Harvard University Graduate School of Arts and Sciences | |
thesis.degree.level | Doctoral | |
thesis.degree.name | Ph.D. | |
dc.contributor.committeeMember | Meyerson, Matthew | |
dc.contributor.committeeMember | Chan, Edmond | |
dc.contributor.committeeMember | Hinds, Philip | |
dc.contributor.committeeMember | Haigis, Kevin | |
dc.type.material | text | |
thesis.degree.department | Medical Sciences | |
dc.identifier.orcid | 0000-0002-5946-7786 | |
dash.author.email | sunjoolee307@gmail.com | |