DNA methyltransferases and their roles in tumorigenesis

Abstract

DNA methylation plays an important role in gene expression, chromatin stability, and genetic imprinting. In mammals, DNA methylation patterns are written and regulated by DNA methyltransferases (DNMTs), including DNMT1, DNMT3A and DNMT3B. Recent emerging evidence shows that defects in DNMTs are involved in tumor transformation and progression, thus indicating that epigenetic disruptions caused by DNMT abnormalities are associated with tumorigenesis. Herein, we review the latest findings related to DNMT alterations in cancer cells and discuss the contributions of these effects to oncogenic phenotypes.

Keywords: DNA methylation; DNA methyltransferases; Tumorigenesis.

Fig. 1

Epigenetic alterations involving DNMTs in tumorigenesis. Numerous clinical and experimental data suggest that tumor cells generally exhibit genome-wide hypomethylation and localized hypermethylation, in contrast with normal cells. Interactions between DNMTs and histone methyltransferases, such as EZH2 and SETD2, play critical roles in epigenetic disruption during malignancy. Thus, the identification of epigenetic alterations involving DNMTs in tumorigenesis may contribute to improved cancer diagnosis and effective treatments

Fig. 2

DNMT3A alterations lead to epigenetic reprogramming in leukemia. Leukemia is a heterogeneous disease caused by cumulative multi-step disruption. In the initial stage of leukemogenesis, accumulated DNA lesions, emergent stimuli, and metabolic stress are observed in hematopoietic stem cells (HSCs). These conditions lead to gene alterations and link epigenetic reprogramming to leukemia development. Currently, DNMT3A gene lesions are considered to be critical epigenetic alterations in the occurrence of leukemia. In patient specimens and mouse models, the mutation or deletion of DNMT3A causes the apparent reversal of normal HSCs into pre-leukemia stem cells (Pre-LSCs). Frequently, Pre-LSCs are quiescent and stable in the early phases of leukemia. The accumulation of other transformative changes, such as a series of mutations (RAS^mut, NPM1^mut, c-Kit^mut) or oncogenic alterations (FLT3^ITD) causes Pre-LSCs to undergo malignant transformation into leukemia stem cells (LSCs), which finally enter the clonal expansion stage. Furthermore, during the aggressive progression of leukemia in a xenograft mouse model of OCI-AML3 with mutated DNMT3A, DNMT3A mutation promotes leukemic extramedullary infiltration by up-regulating the expression of the EMT inducer TWIST1. HSCs: hematopoietic stem cells; Pre-LSCs: pre-leukemia stem cells; LSCs: leukemia stem cells; mut: mutation; del: deletion; ITD: internal tandem duplication; OE: overexpression; EMT: epithelial-mesenchymal transition