Death-associated Protein Kinase 3 (DAPK3), Identified as a Potential Key Factor for the Progression of Ulcerative Colitis (UC), Regulates Intestinal Epithelial Repair
Date
2021-12-14
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Abstract
Ulcerative colitis (UC) is a progressive disorder that elevates the risk of cancer development through a colitis-dysplasia-carcinoma sequence. Recent evidence demonstrates the necessity of Yes-associated protein (YAP) signaling, interceded by cytoskeletal remodeling, for intestinal regeneration. Death-associated protein kinase 3 (DAPK3) is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. In this thesis, DAPK3 was identified as a candidate gene involved in UC progression. Gene ontology (GO) enrichment analysis revealed a shift in transcriptome landscape as UC progressed from left-sided colitis to pancolitis to colitis-associated dysplasia (CAD), from being immune-centric to being cytoskeleton-dependent. Molecular interaction network analysis of genes differentially expressed in left-sided colitis, pancolitis, and CAD revealed one pairwise line or edge that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and DAPK3 was the sole protein kinase associated with this edge. Pharmacological inhibition of DAPK3 in Caco-2 human intestinal epithelial cells (IECs) with the HS38 compound augmented cell proliferation to enhance wound closure. This phenotype corresponded with the increased colocalization of YAP with F-actin, which is indicative of YAP activation. In mice recovering from dextran sodium sulfate (DSS-) induced UC, pharmacological inhibition of DAPK3 increased YAP nuclear localization in IECs, another indicator of YAP activation. However, IEC proliferation was repressed, and mice exhibited increased disease severity when DAPK3 was inhibited with the HS38 compound. It is yet unclear if the incongruous phenotype between the cell and animal studies was the consequence of DAPK3 function on other cell types (e.g., macrophages). In summary, this thesis established DAPK3 as a key factor in intestinal epithelial regeneration and UC progression by way of YAP signaling. Nevertheless, the role that DAPK3 play in different cell types will need further investigation to decipher the full consequence of DAPK3 inhibition on UC progression.
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DAPK3, ZIPK, YAP, Hippo signaling, Ulcerative colitis, Dysplasia, Colon cancer, Intestinal epithelial cell, Proliferation, Wound repair, Differential-gene expression
Citation
Chen, T. H. (2021). Death-associated Protein Kinase 3 (DAPK3), Identified as a Potential Key Factor for the Progression of Ulcerative Colitis (UC), Regulates Intestinal Epithelial Repair (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.