Dysregulation of the PATZ1/CTCF Balance Silences ZBTB20 to Drive Melanoma Progression

The transcription factor PATZ1 exhibits context-dependent roles in human malignancies, yet its biological function and molecular mechanism in melanoma remain incompletely understood. Analysis of public databases and clinical specimens identifies significant PATZ1 overexpression in melanoma tissues, which strongly correlates with advanced disease stage and poor patient survival. Functional investigations demonstrate that PATZ1 drives melanoma cell proliferation, clonogenicity, migration, and invasion across melanoma genetic subtypes in vitro, while promoting tumor growth in vivo. Mechanistically, we discover that PATZ1 binds DNA via a conserved zinc finger domain to competitively displace the chromatin architectural protein CTCF from the promoter region of the tumor suppressor ZBTB20, thereby dysregulating their dynamic binding balance. This DNA-binding-dependent competition collapses a specific CTCF-cohesion-mediated chromatin loop, as directly demonstrated by chromosome conformation capture (3C) assays and validated through integrated multi-omics data and functional enhancer deletion. Genetic rescue experiments confirm that ZBTB20 silencing is essential for PATZ1-mediated oncogenicity. Furthermore, ZBTB20 transcriptionally represses PMEPA1 through direct promoter binding, thereby restraining the pro-tumorigenic p38-STAT1 signaling axis. Our findings define a complete PATZ1/CTCF-ZBTB20-PMEPA1-p38-STAT1 oncogenic pathway and establish that the dysregulation of the PATZ1/CTCF dynamic balance via DNA-binding competition represents a novel epigenetic mechanism driving melanoma progression.

CTCF; PATZ1; ZBTB20; chromatin architecture; melanoma.