Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

Abstract

The histone lysine methyltransferase DOT1L (DOT1-like histone lysine methyltransferase) is responsible for the epigenetic regulation of gene expression through specific methylation of lysine79 residue of histone H3 (H3K79) in actively transcribed genes. Its normal activity is crucial for embryonic development and adult tissues functions, whereas its aberrant functioning is known to contribute to leukemogenesis. DOT1L is the only lysine methyltransferase that does not contain a SET domain, which is a feature that allowed the development of selective DOT1L inhibitors that are currently investigated in Phase I clinical trials for cancer treatment. Recently, abnormal expression of this enzyme has been associated with poor survival and increased aggressiveness of several solid tumors. In this review evidences of aberrant DOT1L expression and activity in breast, ovarian, prostate, colon, and other solid tumors, and its relationships with biological and clinical behavior of the disease and response to therapies, are summarized. Current knowledge of the structural basis of DOT1L ability to regulate cell proliferation, invasion, plasticity and stemness, cell cycle progression, cell-to-cell signaling, epithelial-to-mesenchymal transition, and chemoresistance, through cooperation with several molecular partners including noncoding RNAs, is also reviewed. Finally, available options for the treatment of therapeutically challenging solid tumors by targeting DOT1L are discussed.

Keywords: cancer biomarker; epidrug; histone methyltransferase; small-molecule inhibitor; targeted cancer therapy.

FIGURE 1

Consequences of excessive DOT1L levels on the malignant phenotype of solid tumors.

FIGURE 2

DOT1L mechanism of action and DOT1L inhibitors. DOT1L catalyzes the transfer of the methyl group from the S-adenosyl-L-methionine (SAM) to the lysine 79 residue of the histone H3 (H3K79), introducing a methyl group and releasing the S-adenosyl-L-homocysteine (SAH). On the basis of chemical structure, the DOT1L inhibitors are subdivided into two groups: nucleoside and non-nucleoside DOT1L small-molecule inhibitors. ^* These compounds were described in Perner et al. (2020).