DNMT3A in cancer: from epigenetic writer to oncogenic driver

Cancer is the leading cause of mortality, accounting for one in six deaths worldwide. Despite the emergence of new therapies, cancer mortality remains high. Cancer cells share many traits, such as reprogrammed metabolism and exacerbated proliferation. All these alterations are in part orchestrated by changes in gene expression, notably due to the reshaping of the epigenetic landscape, including DNA methylation marks. Over the past decades, the enzymes responsible for DNA methylation, the DNA methyltransferases (DNMTs), have emerged as important actors in tumorigenesis and therefore as therapeutic targets of choice. Of particular interest is DNMT3A, which plays a critical role in de novo DNA methylation and has been strongly implicated in the pathogenesis of acute myeloid leukemia. Considering the large number of recent studies, this review aims to provide an up-to-date view of knowledge regarding DNMT3A-dependant DNA methylation and its implications for cancer pathophysiology. This review highlights the central position of DNMT3A in cell proliferation, metabolic reprogramming and drug resistance in tumor cells, reinforcing the need for further studies on this protein, which appears to be a key therapeutic target.