DOI
https://doi.org/10.25772/B9JM-CM14
Author ORCID Identifier
https://orcid.org/0000-0001-9922-8555
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Jiong Li
Abstract
The overarching themes of this dissertation work involve unraveling the novel regulation mechanisms of tumorigenesis and identifying therapeutic targets for colorectal cancer (CRC). Abnormal hyperactivation of the Wnt/β-catenin signaling pathway is present in over 90% of CRC cases and plays an important role in CRC initiation and development. Targeting the Wnt/β-catenin pathway for CRC treatment is a sought-after strategy that has unfortunately been unsuccessful thus far. Therefore, there is a continuous need for the elucidation of Wnt/β-catenin regulation in its hyper-activated state to better the understanding of inhibition strategies. The research described herein shows the discoveries of key regulators of oncogenic Wnt/β-catenin signaling, such as histone demethylase proteins, KDM3A/B and KDM5C/D, as potential drug targets for CRC inhibition.
The first project focuses on the small molecule characterization of KDM3 inhibitors. KDM3 and KDM4 histone demethylases were previously reported to promote oncogenic Wnt signaling through demethylation of H3K9 on Wnt target gene promoters. To develop small molecule inhibitors, KDM3 and KDM4 were further characterized regarding their Wnt/β-catenin signaling regulation. KDM3 was found to play a more essential role than KDM4 in regulating oncogenic Wnt signaling in CRC. IOX1, a known histone demethylase inhibitor, was identified to significantly suppress Wnt target gene transcription and CRC tumorigenesis by inhibiting the enzymatic activity of KDM3.
In the second project, histone demethylases, KDM5C and KDM5D, were both identified as regulators of Wnt target gene transcription and Wnt-induced tumorigenesis in CRC through a histone demethylase independent mechanism. This target validation and molecular mechanism study uncovered that KDM5C is a facilitator for the formation of the β-catenin/TCF transcription factor complex by promoting the binding between β-catenin and TCF4, which is key for driving Wnt-related gene expression via recruitment of β-catenin to TCF at Wnt target gene promoters. The interaction domains between KDM5C, β-catenin, and TCF4 were fully characterized for future drug discovery efforts aimed at developing protein-protein interaction inhibitors as traditional enzymatic inhibitors were found to be ineffective. Overall, the research identified novel Wnt/β-catenin regulatory mechanisms by KDM3A/B and KDM5C/D and laid the foundation for future drug discovery and design efforts towards a new treatment strategy for CRC.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-30-2024
Included in
Cancer Biology Commons, Medicinal and Pharmaceutical Chemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, Molecular Biology Commons