锌指转录因子ZFP82通过HDAC3调控p53蛋白稳定性增敏食管癌新辅助化疗的作用和机制

食管癌死亡率高，总体生存率低。部分患者对新辅助化疗抵抗是食管癌治疗中存在的重要瓶颈之一，但具体机制不清楚。我们前期研究发现启动子甲基化调控的ZFP82沉默与化疗抵抗密切相关；ZFP82抑制组蛋白去乙酰化酶HDAC3可以增敏化疗；HDAC3通过不同机制使野生型p53去乙酰化，突变型p53稳定性增强。本研究提出“ZFP82通过HDAC3调控p53蛋白稳定性增敏食管癌新辅助化疗”的假说，我们拟通过癌组织标本、裸鼠模型及耐药细胞模型，1）明确ZFP82增敏新辅助化疗的作用；2）阐明ZFP82调控HDAC3在野生型和突变型p53信号通路的双重作用机制；3）论证ZFP82表达和甲基化与食管癌新辅助化疗疗效的关系，可否作为判定食管癌新辅助化疗疗效的靶标。本项目有望从表观遗传角度，为食管癌新辅助化疗探索增敏靶点及制订精准治疗策略提供重要参考。

Esophageal cancer has high mortality rate and low overall survival. Some patients experienced non-response to neo-adjuvant chemo-therapy . Understanding the mechanisms of its resistance to chemo-therapy is of great significance in esophageal cancer treatment. Our group previously identified ZFP82 was silenced by promoter methylation in non-responders. ZFP82 may transcriptionally repress HDAC3 and inhibit the deacetylation function of HDAC3 , which in turn enhances the acetylation of p53 and degradation of mutation p53.Through this process ,ZFP82 may be involved in chemo-resistance of esophageal cancer. So we proposed the hypothesis ZFP82 enhances neo-adjuvant chemotherapy sensitivity in esophageal cancer through interacting with HDAC3. By in vivo and in vitro experiments and analysis of patient tissue samples, we planned to reveal the function of ZFP82 in chemo- resistance; to understand the mechanism of how ZFP82 interacting with HDAC3, its involvement in chemo-resistance; and to verify the correlation between ZFP82 methylation and non-response to neo-adjuvant chemotherapy in esophageal cancer. This study provides evidence of an epigenetic biomarker which predicts the outcome of chemo-therapy and helps developing precise treatment for esophageal cancer patients.