ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma
CELL DEATH & DISEASE
Authors: Wu, Yi-Ju; Ko, Bor-Sheng; Liang, Shu-Man; Lu, Yi-Jhu; Jan, Yee-Jee; Jiang, Shih-Sheng; Shyue, Song-Kun; Chen, Linyi; Liou, Jun-Yang
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 14-3-3 epsilon, and MT-1 overexpression abolished 14-3-3 epsilon-induced cell proliferation and tumor growth. We identified that 14-3-3 epsilon induced expression of ZNF479, a novel potential transcriptional regulator by gene expression profiling and ZNF479 contributed to 14-3-3 epsilon-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) dimethylation. 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.
Clinicopathologic and genetic spectrum of infantile B-lymphoblastic leukemia: a multi-institutional study
LEUKEMIA & LYMPHOMA
Authors: Knez, Virginia; Liu, Xin; Schowinsky, Jeffrey; Pan, Zenggang; Wang, Dehua; Lorsbach, Robert; Lu, Chuanyi; Luedke, Catherine; Haag, Mary; Carstens, Billie; Swisshelm, Karen; Yang, Lian-He; Jug, Rachel; Wang, Endi; Liang, Xiayuan
Abstract
Acute lymphoblastic leukemia (ALL) in infants KMT2A rearrangement is the predominant genetic signature in infantile B-ALL, disease course is heterogenous, behaving more aggressively in younger infants. We investigated clinicopathological differences throughout the first year to understand the transition to pediatric B-ALL. In a multi-institutional review involving four medical institutions, 54 cases of infantile B-ALL were identified. Patients were divided into congenital and non-congenital groups with multiple age subgroups. Male predominance was seen in congenital cases compared to female in non-congenital cases. There were decreasing trends of hyperleukocytosis, central nervous system involvement, KMT2A rearrangements, lineage switch, and mortality, versus increasing trends of CD10 expression and non-KMT2A abnormalities. Statistically significant differences emerged at 3 and 9 months, the latter was not previously described. Poor-prognostic risk factors decreased with age, the last trimester of infantile B-ALL essentially merging with pediatric B-ALL.