Abstract 2558: Regulation of the expression of the DNA repair endonuclease 8-like 3 gene in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy in the world, but the molecular mechanism of HCC development is still unclear. Previous studies had showed that the endonuclease 8-like 3 (Neil3) gene, a DNA glycosylase for oxidative DNA repair, overexpressed in most of cancers including HCC. In our previous cDNA microarray analysis in HCC tissues, it was found that the Neil3 gene was highly expressed in mouse and human tumors. The results of real-time RT-PCR analysis in 113 HCC patients showed that the Neil3 gene mRNA was increased in most human tumors. The Neil3 gene expression levels were also highly correlated with HCC recurrence in the patients receiving the hepatectomy surgeries, suggesting that it can serve as a prognostic marker for HCC. In this study we characterized the molecular mechanisms of the Neil3 gene expression regulation in HCC. We analyzed the methylation status in the Neil3 gene promoter regions by DNA methylation array (Agilent) and found that the Neil3 gene promoter was hypo-methylated in HCC tumors. Also, by the promoter reporter assays it was found that the main regulatory region for its transcription activity was from -123 to +94 upstream to the transcription start site. Furthermore, the DNA affinity precipitation assay (DAPA) was performed to screen for the transcription factors that bind to the Neil3 promoter and identified that cell cycle regulator E2F1, Yin Yang 1 (YY1) and histone deacetylase 1 (HDAC1) bind to the Neil3 gene promoter. It suggested that E2F1, YY1 and HDAC1 play important roles in regulating Neil3 gene expression. These transcription factors have been known to enhance cell proliferation and potentially the NEIL3-mediated oncogenic properties. And treatments of the HDAC inhibitor SAHA increased the Neil3 mRNA and protein levels. The functional effects of these pro-oncogenic transcriptional factors to the NEIL3-relevant HCC progression are currently in investigation. The results of these studies will clarify the regulatory mechanisms for the Neil3 gene induction in HCC progression. Citation Format: Wenya Huang. Regulation of the expression of the DNA repair endonuclease 8-like 3 gene in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2558.