Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity

Abstract

DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPA N321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPA N321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA -mutated leukemia with DNA-hypomethylating agents.

Emerging role of different DNA methyltransferases in the pathogenesis of cancer

“…In addition, the transcription factor CCAAT enhancer-binding protein alpha (CEBPA) controls lineage-specific gene expression and is mutated in a subset of AML ( Mannelli et al, 2017 ). In a significant analysis and discussion on oncogenic role of DNMT3A in AML, Chen et al (2022) revealed that CEBPA interacted with DNMT3A N terminus (a required structure for normal development and DNA methylation at DNMT3A1-enriched regions) ( Gu et al, 2022 ), preventing DNMT3A from binding DNA and catalyzing CpG methylation. Once cancer-associated mutations in CEBPA, it relieved DNMT3A inhibition and promoted AML.…”

Germline structural variation globally impacts the cancer transcriptome including disease-relevant genes

“…Interestingly, CEBPA itself is understood to represent a tumor suppressor gene, particularly in leukemia. 32 However, long non-coding RNA CEBPA-DT , a divergent transcript of CEBPA , has recently been found to promote liver cancer metastasis through DDR2/β-catenin activation. 33 , 34…”

Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia

“…In contrast, deletion of CEBPA blocks normal granulocyte formation and prevents initiation of AML 49,50 . Overexpression of wild-type C/EBPα has no effect on cell proliferation in K562 leukaemia cells 51 but decreases the growth rate by 2.7-fold in U937 lymphoma cells 52 . In the clinic, both FLT3-ITD and CEBPΑ mutations were relatively mutually exclusive, with 5-10% and 1% FLT3 mutations in CEBPΑsm (single mutation) and CEBPΑdm (double mutation) patients, respectively [53][54][55] .…”