TFAP2E (transcription factor AP-2 epsilon) is a sequence-specific DNA-binding transcription factor that plays critical roles in embryonic development and cancer biology. TFAP2E functions as a transcriptional regulator that binds to specific DNA sequences and controls gene expression programs essential for central nervous system, orofacial, and maxillofacial development 1. In zebrafish models, loss of tfap2e results in hydrocephalus, reduced brain volume consistent with microcephaly, and orofacial anomalies, demonstrating its crucial role in neural development 1. In cancer contexts, TFAP2E exhibits tumor-suppressive properties, with its expression frequently silenced through promoter hypermethylation 234. TFAP2E hypermethylation is significantly associated with chemotherapy resistance, particularly to fluorouracil-based treatments in colorectal and gastric cancers 23. The mechanism involves TFAP2E regulation of DKK4, where loss of TFAP2E expression leads to increased DKK4 levels and subsequent chemoresistance 2. Additionally, TFAP2E can be regulated by metabolic factors, as squalene accumulation can interfere with TFAP2E promoter activity through Sp1 binding, affecting mitochondrial metabolism 5. Clinically, TFAP2E methylation status serves as a potential biomarker for predicting chemotherapy response in cancer patients 23.