Zic family member 5 (ZIC5)

Zic family member 5 (ZIC5) is a member of the Zinc finger of the cerebellum (ZIC) family of transcription factors, characterized by five highly conserved C2H2-type zinc finger domains [1, 3]. It plays a pivotal role in early embryonic development, specifically in neural crest specification, neural tube closure, and skeletal patterning [5, 12]. In adult tissues, ZIC5 expression is largely restricted to the brain and testes, but it is frequently overexpressed in various cancers, including melanoma, hepatocellular carcinoma, and lung adenocarcinoma [1, 4, 30]. In these malignancies, ZIC5 acts as an oncogenic driver by promoting cell proliferation, epithelial-mesenchymal transition (EMT), and metastasis through the regulation of downstream targets like PDGFD and E-cadherin [21, 31, 34]. Furthermore, ZIC5 is implicated in therapeutic resistance, particularly to BRAF inhibitors in melanoma, making it an attractive candidate for targeted cancer therapy [30, 31]. While currently considered a challenging target for small molecules, experimental inhibitors and pathway-directed therapies are under investigation to mitigate its role in tumor progression [20, 35].

Other names

Zic family zinc finger 5Zinc finger protein of the cerebellum 5Zinc finger protein ZIC 5Odd-paired homolog (Drosophila)

ZIC5 acts as a transcriptional regulator that binds to specific DNA sequences via its C2H2 zinc finger domains to modulate the expression of genes involved in cell growth and metastasis, such as PDGFD and CDH1. It also functions as a cofactor in the Wnt/beta-catenin signaling pathway by interacting with the TCF4 complex to enhance the transcription of oncogenic targets.