ZNF750 loss defines an ESCC subtype with constitutive NF-κB activation and vulnerability to bortezomib

Esophageal squamous cell carcinoma (ESCC) lacks effective targeted therapies. The tumor suppressor ZNF750 is frequently inactivated, yet the primary mechanism and its therapeutic implications remain poorly defined.

We performed an integrated multi-omics analysis on a large ESCC cohort (n = 767). Mechanistic insights were validated by ChIP-qPCR, luciferase assays, and functional studies in vitro and in vivo.

ZNF750 was transcriptionally silenced in 93.5% of tumors, and this was primarily driven by highly activated NF-κB signaling rather than genetic alteration. We identified a pathogenic feedback loop: NF-κB1(12-fold enrichment on the ZNF750 promoter) represses ZNF750 transcription, while ZNF750 protein suppresses the expression of CARD14, a potent NF-κB activator (mRNA reduced by >70% upon ZNF750 re-expression). ZNF750 loss thereby licenses constitutive NF-κB signaling. Crucially, ZNF750-deficient tumors exhibited heightened sensitivity to the NF-κB-inhibiting proteasome inhibitor, bortezomib, both in cell lines (IC50) and patient-derived xenograft models.

Our findings establish NF-κB-mediated repression as the principal mechanism silencing ZNF750 in ESCC. We define ZNF750 loss as a novel biomarker for patient stratification and provides a strong rationale for the clinical evaluation of bortezomib for this molecularly defined ESCC subtype, offering a mechanistic rationale for a biomarker-driven therapeutic strategy for most ESCC patients.