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

  • Biochim Biophys Acta Mol Basis Dis. 2026 Aug;1872(6):168282. doi: 10.1016/j.bbadis.2026.168282.
Yanghui Bi  1 ,  Mengyao Wang  2 ,  Yong Zhang  3 ,  Heyang Cui  4 ,  Caixia Cheng  5 ,  Bin Song  6 ,  Ling Zhang  7 ,  Pengzhou Kong  7 ,  Bin Yang  8 ,  Fajia Yuan  9 ,  Ruiping Zhang  10 ,  Yongping Cui  11
Affiliations
  • 1. Center of Gene Sequencing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China; Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research of Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
  • 2. Shanxi Academy of Medical Sciences, Shanxi Medical University, Taiyuan, 030001, China.
  • 3. Endoscopic Center of Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China.
  • 4. Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
  • 5. Department of Pathology, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
  • 6. Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
  • 7. Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research of Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
  • 8. Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, 030001, China.
  • 9. Jinzhong Vocational and Technical College, Jinzhong, 030600, China.
  • 10. The Radiology Department of Shanxi Provincial People's Hospital, The Fifth Hospital of Shanxi Medical University, Taiyuan, 030001, China. Electronic address: [email protected].
  • 11. Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research of Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi, 030001, China. Electronic address: [email protected].
PMID: 42086128 DOI: 10.1016/j.bbadis.2026.168282
Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Keywords
Biomarker; Bortezomib; Drug repurposing; ESCC; NF-κB; ZNF750.
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