DNMT3A promotes the proliferation and metastasis of esophageal squamous cell carcinoma via upregulating HDAC9

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and is characterized by high morbidity and mortality. However, the detailed molecular mechanisms underlying malignant progression of ESCC remain unclear. Methods 140 patients with esophageal squamous cell carcinoma who underwent surgery were enrolled in this study. Clinicopathologic characteristics and Kaplan–Meier survival analysis were performed to investigate DNMT3A expression and HDAC9 expression. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on ESCC cell proliferation and metastasis. Recombinant lentivirus–meditated gene overexpression or knockdown showed that HDAC9 participated in DNMT3A-mediated ESCC progression in vivo and in vitro, and this was further confirmed by HDAC inhibitor (SAHA) and immunohistochemical. Results We first demonstrated that DNMT3A expression was significantly higher in ESCC tissues than in corresponding adjacent non-cancerous tissues, and high DNMT3A expression was associated with poor prognosis. Then we confirmed that DNMT3A promoted proliferation and metastasis of ESCC cells in vivo and in vitro, suggesting that DNMT3A may be a promising therapeutic target for preventing esophageal cancer. Additionally, we found that DNMT3A up-regulated HDAC9, and HDAC9 overexpression significantly reversed the inhibitory effect caused by DNMT3A gene knockdown. In addition, we further confirmed the involvement of HDAC9 in DNMT3A-mediated carcinogenesis using HDAC inhibitor (SAHA). At last, we also validated HDAC9 expression was significantly higher in ESCC tissues than in corresponding adjacent non-tumour tissues, and high HDAC9 expression was positively associated with poor prognosis. Interestingly, Spearman correlation analysis confirmed a significant positive correlation between DNMT3A and HDAC9 expression. and ESCC patients with simultaneous DNMT3A and HDAC9 expression have the worst prognosis. Conclusions These results suggest that HDAC9 is involved in DNMT3A-mediated progression of ESCC, and targeting DNMT3A and HDAC9 may be a potential ESCC therapeutic strategy.