Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia.

The gene encoding the tumor suppressor p53 is the most frequently mutated gene in cancers. However, p53 mutation is rare in acute myeloid leukemia (AML), and p53 is inactivated predominantly by aberrant expression of p53 regulators (such as MDM2). A previous study by the authors revealed that the ZCCHC10 protein suppressed MDM2‑mediated degradation of the p53 protein in lung cancer. However, the expression and role of the ZCCHC10 gene in AML have not been investigated. In the present study, it was found that ZCCHC10 expression was downregulated in bone marrow samples of AML patients and that ZCCHC10 expression was significantly and negatively correlated with the expression of the lncRNA SNHG1. Suppression of SNHG1 decreased ZCCHC10 promoter methylation and increased ZCCHC10 expression. Notably, there is a putative binding motif in SNHG1 with full complementarity to five sites surrounding the CpG island in the ZCCHC10 promoter. Overexpression of wild‑type SNHG1 promoted ZCCHC10 methylation, but overexpression of SNHG1 with deletion of the binding motif did not. Further study identified that SNHG1 simultaneously bound to the ZCCHC10 promoter and the DNA methyltransferases DNMT1 and DNMT3B. These results indicated that SNHG1 recruits DNMT1 and DNMT3B to the ZCCHC10 promoter, resulting in hypermethylation of the ZCCHC10 promoter. Kaplan‑Meier survival analysis showed that ZCCHC10 expression was positively associated with overall survival in AML patients.