Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schweighofer, J.
Targeting epigenetic regulators in bladder cancer by the BET inhibitor JQ1
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2018. pp. 58
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Hutter Heinz
- Altmetrics:
- Abstract:
- Urothelial bladder cancer is among the five most common cancers diagnosed in the United States and causes significant mortality and morbidity rates as well as a reduction in quality of live in affected patients. Therapeutic strategies to target the disease depend on the extent of local muscle invasion and comprise surgical resection, immunotherapy and chemotherapy. On the molecular level, UBC is characterized by high rates of somatic mutations, including several groups of epigenetic regulatory genes such as chromatin modifiers or nucleosome remodelers. Noteworthy, a recent study showed that mutations in these enzymes are likely to have profound impacts on the regulation and expression of various transcription factors and pathways involved in UBC, suggesting that inhibition of epigenetic regulatory mechanisms might repress tumor progression. Our main focus will be BRD4. It is an epigenetic reader protein of acetylated histones that has recently been shown to be involved in the regulation of oncogenes such as c-Myc (REF) and belongs to the bromodomain and extra-terminal family. They play a vital part in the regulation of gene transcription by binding to acetylated histones and non-histone proteins and associating with transcription factors. JQ1 is a small molecular compound that has the ability to bind competitively to acetyl-lysine recognition motifs found in BET proteins. Binding of JQ1 to these motifs leads to a displacement of BET bromodomains and prevents, for example, BRD4 activity, with a direct effect on transcription. JQ1 treatment has shown to have antiproliferative effects in several cancer types. In non-muscle invasive bladder cancer, JQ1 led to an inhibition of proliferation and G1 cell-cycle arrest and induced immediate and progressive apoptosis in BRD4 depending cells. In this project, we aim to analyze the influence of JQ1 on a panel of UBC cell lines and characterize its effect on UBC and on epigenetic regulatory mechanisms pharmacologically and on a molecular level. We also will determine transcriptional targets of BRD4 and detect molecular pathways involved in BRD4 mediated transcription. To determine the effect of JQ1 and to establishing IC50 doses on our UBC cell lines, we administered increasing concentrations of JQ1, staring form 0.01 µM to 1000µM. We also investigated protein expression of BRD4 via Western blotting and looked at gene expression using qPCR. We observed that JQ1 might be viable future treatment option in UBC. However it might be of importance to look at the expression pattern of a variety of oncogenes. Especially Myc genes are of special interest, to distinguish which cancer might be responsive to JQ1 and which one might rather profit from a combination treatment of JQ1 with other agents such as MMC or Romidepsin. This could lead to the development of an individualized and a more tailored treatment of cancer patients.