Molecular Network Analyses Implicate Death-Associated Protein Kinase 3 (DAPK3) as a Key Factor in Colitis-Associated Dysplasia Progression

Abstract

Background Ulcerative colitis (UC) is a progressive disorder that elevates the risk of colon cancer development through a colitis-dysplasia-carcinoma sequence. Gene expression profiling of colitis-associated lesions obtained from patients with varied extents of UC can be mined to define molecular panels associated with colon cancer development. Methods Differential gene expression profiles of 3 UC clinical subtypes and healthy controls were developed for the GSE47908 microarray data set of healthy controls, left-sided colitis, pancolitis, and colitis-associated dysplasia (CAD) using limma R. Results A gene ontology enrichment analysis of differentially expressed genes (DEGs) revealed a shift in the transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein [YAP]) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. A molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed 1 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 death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase member of this network. Death-associated protein kinase 3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls that flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive. Conclusion In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia.

Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

“…Thus, the inhibition of DAPK3 may serve as a strategy for the treatment of cardiovascular diseases. 156 It was reported that DAPK3 is down-regulated in ulcerative colitis (UC), but the mechanism is unclear 157 (Table 3).…”

Death‐associated protein kinases and intestinal epithelial homeostasis

“…In addition to these molecular participants, a role for DAPK3 in epithelial restitution is sensible given the molecular functions assigned to the kinase. In fact, Hippo/Wnt signaling and a molecular network of differentially expressed genes (i.e., DEGs) that included DAPK3 was uniquely identified as a determinant for colitis‐dysplasia progression (Chen & MacDonald, 2022). The results further support a potential regulatory relationship among DAPK3, YAP/TAZ, and actin cytoskeletal dysregulation in the advancement of disease from pancolitis to dysplasia.…”

“…With its demonstrable involvement in key signaling pathways that could facilitate epithelial regeneration after injury, it is tempting to speculate that DAPK3 may play a role in epithelial restitution and wound healing required for the resolution of colitis. In this regard, DAPK3 was recently identified as a determinant for the progression of UC from nondysplastic to dysplastic (Chen & MacDonald, 2022). However, the precise molecular actions of DAPK3 within the context of colitis or colitis‐associated dysplasia–carcinoma have yet to be elucidated.…”