Back to Search
Start Over
ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma.
- Source :
-
Cell death & disease [Cell Death Dis] 2019 May 28; Vol. 10 (6), pp. 408. Date of Electronic Publication: 2019 May 28. - Publication Year :
- 2019
-
Abstract
- Decreased expression of metallothionein-1 (MT-1) is associated with a poor prognosis in hepatocellular carcinoma (HCC). Here, we found that MT-1 expression was suppressed by 14-3-3ε, and MT-1 overexpression abolished 14-3-3ε-induced cell proliferation and tumor growth. We identified that 14-3-3ε induced 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. Moreover, correlations between the expression of ZNF479 and its downstream factors were more pronounced in HCC patients with hepatitis B. Here, we found that ZNF479 regulates MT-1 expression by modulating ASH2L in HCC. Approaches that target ZNF479/MLL complex/MT-1 or related epigenetic regulatory factors are potential therapeutic strategies for HCC.
- Subjects :
- 14-3-3 Proteins genetics
14-3-3 Proteins metabolism
Animals
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular pathology
Cell Proliferation drug effects
Cell Proliferation genetics
DNA (Cytosine-5-)-Methyltransferase 1 genetics
DNA-Binding Proteins genetics
Elafin antagonists & inhibitors
Elafin genetics
Elafin metabolism
Hep G2 Cells
Histones metabolism
Humans
Liver Neoplasms genetics
Liver Neoplasms pathology
MAP Kinase Signaling System drug effects
MAP Kinase Signaling System genetics
Metallothionein genetics
Methylation
Mice
Mice, Inbred BALB C
Mice, Nude
Nuclear Proteins genetics
TOR Serine-Threonine Kinases antagonists & inhibitors
TOR Serine-Threonine Kinases genetics
TOR Serine-Threonine Kinases metabolism
Transcription Factors genetics
Transplantation, Heterologous
Carcinoma, Hepatocellular metabolism
DNA (Cytosine-5-)-Methyltransferase 1 metabolism
DNA-Binding Proteins metabolism
Liver Neoplasms metabolism
Metallothionein metabolism
Nuclear Proteins metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 10
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 31138789
- Full Text :
- https://doi.org/10.1038/s41419-019-1651-9