Decreased expression of metallothionein-1 (MT-1) is associated with a poor prognosis in hepatocellular carcinoma (HCC). Dr. Jun-Yang Liou and his team from the Institute of Cellular and System Medicine reported that MT-1 expression was suppressed by 14-3-3ε, and MT-1 overexpression abolished 14-3-3ε-induced cell proliferation and tumor growth. The team identified that 14-3-3εinduced expression of ZNF479, a novel potential transcriptional regulator by gene expression profiling and ZNF479 contributed to 14-3-3ε-suppressed MT-1 expression. ZNF479 induced the expression of DNMT1, UHRF1, and mixed-lineage leukemia (MLL) complex proteins (ASH2L and Menin), and increased tri-methylated histone H3 (H3K4me3) levels, but suppressed H3K4 (H3K4me2) di-methylation. ZNF479-suppressed MT-1 expression was restored by silencing of ASH2L and DNMT1. Furthermore, ZNF479 expression was higher in HCC tissues than that in the non-cancerous tissues. Expression analyses revealed a positive correlation between the expression of ZNF479 and DNMT1, UHRF1, ASH2L, and Menin, and an inverse correlation with that of ZNF479, ASH2L, Menin, and MT-1 isoforms. In addition, correlations between the expression of ZNF479 and its downstream factors were more pronounced in HCC patients with hepatitis B.
The team found that ZNF479 regulates MT-1 expression by modulating ASH2L in HCC, and developing approaches that target ZNF479/MLL complex/MT-1 or related epigenetic regulatory factors are potential therapeutic strategies for HCC. These findings have been published on Cell Death and Disease (2019 May 28;10(6):Article number 408).
Citation: Wu, YJ; Ko, BS; Liang, SM; Lu, YJ; Jan, YJ; Jiang, SS; Shyue, SK; Chen, L; Liou, JY. ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma. Cell Death and Disease. 2019 May 28;10(6):Article number 408.