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Integrated Characterization of AP-2δ Reveals Distinct Regulatory Architecture in Lung Adenocarcinoma and Lung
Damian Kołat1,2, Weronika Kruczkowska1,3, Żaneta Kałuzińska-Kołat1,2
1Department of Functional Genomics, Medical University of Lodz, 90-752 Lodz, Poland.
Abstract:
Background/Objectives: AP-2δ, encoded by TFAP2D, is one of the least characterized members of the AP-2 transcription factor family, although available evidence suggests biologically relevant roles in lung cancer that have not yet been thoroughly examined. The aim of the present study was to provide an integrated characterization of AP-2δ/TFAP2D in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Methods: LUAD and LUSC data were obtained from The Cancer Genome Atlas. The analysis comprised the expression profiling of AP-2δ target genes, survival-guided TFAP2D stratification, clinical profiling, differential expression and intersection analyses, methylation-derived chromatin compartment profiling, TFAP2D-associated cofactor rewiring, and genome-wide enrichment of AP-2δ targets. In parallel, pocket prioritization was performed using an AlphaFold model of AP-2δ with cross-tool consensus mapping. Results: TFAP2D stratification delineated biologically-distinct states in both histological subtypes (LUAD and LUSC). AP-2δ target genes showed subtype-specific expression patterns and functional organization. The consistent survival association was observed for progression-free interval rather than uniformly across all endpoints. Clinical profiling was more closely associated with molecular subtype composition than broad clinicopathological differences. Differential expression analyses identified both shared and histology-dependent programs associated with TFAP2D. In the chromatin-compartment analysis, LUSC showed a broader and more coherent footprint, whereas LUAD displayed more selective cofactor rewiring. Structure-based analysis prioritized a small set of reproducible candidate pockets concentrated within ordered regions of the TF_AP-2 domain. Conclusions: AP-2δ marks biologically meaningful but histologically non-uniform regulatory states in lung cancer. These findings provide an integrated framework for understanding TFAP2D-dependent regulation in LUAD and LUSC, highlighting AP-2δ as a candidate for future mechanistic and translational investigation.
Insights
AP-2δ (TFAP2D) plays a role in lung cancer, marking distinct regulatory states in lung adenocarcinoma and squamous cell carcinoma. Further research into AP-2δ could lead to new lung cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- AP-2δ (TFAP2D) is a poorly understood transcription factor with suggested roles in lung cancer.
- Previous research has not thoroughly investigated its function in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
Purpose of the Study:
- To comprehensively characterize AP-2δ/TFAP2D in LUAD and LUSC.
- To explore its regulatory roles and potential as a therapeutic target in lung cancer subtypes.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) data for LUAD and LUSC.
- Expression profiling of AP-2δ target genes, survival analysis, clinical and differential expression profiling.
- Chromatin compartment analysis, cofactor rewiring, and structure-based pocket prioritization using AlphaFold.
Main Results:
- TFAP2D stratification identified distinct biological states within LUAD and LUSC.
- AP-2δ target genes exhibited subtype-specific expression and functional patterns.
- Progression-free interval showed consistent survival association; clinical profiles linked more to molecular subtypes than clinicopathology.
- Differential expression revealed shared and histology-dependent programs; chromatin analysis showed subtype-specific footprints and cofactor rewiring.
- Structure-based analysis identified candidate pockets within the TF_AP-2 domain.
Conclusions:
- AP-2δ regulates biologically significant but heterogeneous states in lung cancer.
- Provides an integrated framework for TFAP2D-dependent regulation in LUAD and LUSC.
- Highlights AP-2δ as a promising candidate for future mechanistic and translational lung cancer research.
