Date of Award
Master of Science
Douglas A. Steeber
Julie A. Oliver, Dean T. Nardelli
Acetylation, Drug therapy, Epigenetics, HDAC, HDAC inhibitors, Histone
Epigenetic dysregulations are linked to many human diseases including neurodegenerative disorders, immunodeficiencies, cardiac disease, and most notably cancer. Changes in the mechanisms of histone modifications have been recognized as hallmarks of carcinogenesis. One of these modifications is histone acetylation which is regulated by the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The reversible actions of these enzymes govern the acetylome and maintain its balance allowing for activation and repression of gene transcription. However, aberrant overexpression of HDACs in certain tumors is associated with decreased levels of transcription leading to tumor progression and survival. Hence, small-molecule histone deacetylase inhibitors (HDACi) have been developed to target the overexpression of HDACs. Currently, there are four FDA-approved HDACi used in therapy (SAHA, FK228, bleinostat, and panobinostat) for cancer treatment and many others are under investigation. Despite their success in treating T and B cell lymphoma, the use of HDACi as monotherapeutic agents in treating solid tumors has been limited due to their lack of specificity for HDAC isoforms, increased toxicity, and poor uptake by tumor cells. Therefore, we hypothesize that treatment with novel small molecule histone deacetylase inhibitors developed at UWM will result in decreased proliferation of tumor cell lines and increased histone H3 acetylation. The present hypothesis was tested by comparing the antiproliferative activity of novel compounds in the adherent DU145 prostate cell line and the nonadherent Jurkat T cell line. Using a cell proliferation assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)), a lead HDACi compound called MJM-1 was identified based on its ability to inhibit tumor cell proliferation in a dose-dependent manner. Using fluorescence microscopy and flow cytometry, MJM-1 was demonstrated to increase histone acetylation in DU145 cells. Collectively, this work provides an initial assessment of MJM-1 and its potential for future use.
Alanani, Samer, "Evaluating the Biological Activities of Novel Histone Deacetylase Inhibitors (hdaci) in Adherent and Nonadherent Tumor Cell Lines" (2021). Theses and Dissertations. 2970.
Available for download on Thursday, March 14, 2024