| dc.contributor.advisor | Johnsen, Steven Prof. Dr. | |
| dc.contributor.author | Wang, Xin | |
| dc.date.accessioned | 2021-01-08T10:27:25Z | |
| dc.date.available | 2021-09-30T00:50:25Z | |
| dc.date.issued | 2021-01-08 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0005-153B-2 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8368 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8368 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | The Role of BRDT in Esophageal Squamous Cell Carcinoma | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Johnsen, Steven Prof. Dr. | |
| dc.date.examination | 2020-10-02 | |
| dc.description.abstracteng | Esophageal squamous cell carcinoma (ESCC), the predominant subtype of esophageal cancer, remains a deadly malignancy due to the lack of effective therapies. Precision oncology, utilizing various techniques to identify patient-specific vulnerabilities for therapeutic intervention, has emerged as a promising approach for cancer treatment. Many clinical trials involving EGFR-targeted therapies in ESCC have failed, highlighting a need for the identification of novel therapeutic targets. Epigenetic alteration is one of the hallmarks of cancer and epigenetic factors are also widely dysregulated in ESCC. In this project, we sought to identify a therapeutic target for advancing precision medicine in ESCC. Using an unbiased method, we screened a curated list of epigenetic factors and found that a testis-specific epigenetic reader protein BRDT to be expressed and functional active in a significant portion of ESCC patients. While it does not affect cell proliferation, it is essential for cell migration. Transcriptomic profiling revealed extracellular matrix-related pathways are altered upon loss of BRDT, which could explain the decreased migratory potential. Chromatin occupancy profiling of BRDT uncovered its preferential occupancy of active promoters and enhancers. Subsequently, we found that genes dependent on BRDT are also targets of ΔNp63, a master transcription factor for squamous lineage commitment. Besides the common target genes, genomic co-localization of BRDT and ΔNp63 confirms the functional interplay between them. Knock-down of ΔNp63 or FAT2, a common target of BRDT and ΔNp63, phenocopies the loss of BRDT. Furthermore, overexpression of BRDT in a BRDT-negative ESCC cell line can enhance the expression of the ΔNp63-dependent gene expression program and significantly increase cell migration. To gain more mechanistic insight, we integrated chromatin topology data with epigenome profiles and found that BRDT and ΔNp63 co-localize at selected super enhancers to regulate ΔNp63-dependent transcription programs that promote cell migration. Strikingly, pharmacologically depleting BRDT recapitulates the effects of BRDT depletion. Collectively, these findings revealed the role of BRDT in ESCC and uncover the potential of BRDT as a novel therapeutic target for precision medicine in a subset of ESCC. | de |
| dc.contributor.coReferee | Dobbelstein, Matthias Prof. Dr. | |
| dc.subject.eng | Bromo- and Extraterminal Domain | de |
| dc.subject.eng | Esophageal Cancer | de |
| dc.subject.eng | Epigenetics | de |
| dc.subject.eng | Chromatin | de |
| dc.subject.eng | ΔNp63 | de |
| dc.subject.eng | Precision oncology | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-153B-2-6 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2021-09-30 | |
| dc.identifier.ppn | 1744275513 | |