Zinc Finger Protein ZFP82 regulates p53 protein stability through histone deacetylase 3 and enhances neo-adjuvant chemotherapy in esophageal cancer

We previous revealed Zinc-Finger Protein 82 (ZFP82) was highly methylated in multiple cancers, including esophageal cancer. Here we show that ZFP82 is highly methylated in patients who experienced non-responders in Neoadjuvant chemotherapy compared to those who are pathological complete response by Infinium Methylation EPIC Bead Chip. The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. We verified here that ZFP82 bound to HDAC3 promoter and mediated its interaction with p53, which induced HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Ectopic ZFP82 induced p53 stabilization and HDAC3 cleavage, indicating an essential role of ZFP82 in p53 activation. Restoration of ZFP82 restored the chemo-sensitivity in esophageal cancer cell both expressing wild type p53 and mutant p53, significantly inhibited in vivo tumorigenicity of esophageal cells and correlated with better prognosis in patients. Our results define a mechanism for p53 stabilization via ZFP82-dependent HDAC3 decay under genotoxic stress conditions and validated a candidate bio-marker of early prediction of patients responds to esophageal cancer Neoadjuvant chemotherapy.