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.

Epigenetics and environment in breast cancer: New paradigms for anti-cancer therapies

“…One of the only known histone 3 lysine 79 (H3K79) methyltransferases, is the histone methylase disruptor silencing 1 like (DOT1L) which has critical role in the development of breast cancer and is a potential therapeutic target for invasive breast cancer ( 124 , 125 ). DOT1L is known to facilitate the aggressiveness of tumors by elevating the metastatic behavior of cancer cells ( 126 ) and is implicated in lymph node metastasis of breast cancer ( 127 ).…”

Combinatorial targeting of a chromatin complex comprising Dot1L, menin and the tyrosine kinase BAZ1B reveals a new therapeutic vulnerability of endocrine therapy-resistant breast cancer

“…In mixed-lineage leukemia, for example, this enzyme associates with MLL fusion proteins, sustaining leukemogenesis via transcriptional regulation mechanisms, and its inhibitors have been clinically tested as therapeutic targets for leukemias carrying this genetic vulnerability [ 9 ]. The potential of Dot1L pharmacological blockade for therapy has been demonstrated also in ovarian, prostate and other cancers [ 8 , 10 – 13 ]. For solid tumors, Dot1L inhibitors are still far from clinical use, in particular for problems caused by their low tolerability and severe side effects.…”

Combinatorial targeting of menin and the histone methyltransferase DOT1L as a novel therapeutic strategy for treatment of chemotherapy-resistant ovarian cancer

“…Other studies highlighted ERα-independent DOT1L role in OC mediated by transcriptional regulation of cell cycle [ 5 ] and multi-drug resistance genes [ 6 ] and suggested DOT1L as a valuable prognostic biomarker in OC. Evaluation of therapeutic potential of DOT1L pharmacological inhibition has proved to be effective in treatment of multiple cancer types including ovarian, breast, prostate and other solid tumours (reviewed in [ 7 ]). However, DOT1L inhibitors use in clinics is still hampered by low tolerance and severe side effects caused by drug administration indicating to the need of therapeutic efficacy improvement for these epigenetic drugs [ 7 ].…”

“…Evaluation of therapeutic potential of DOT1L pharmacological inhibition has proved to be effective in treatment of multiple cancer types including ovarian, breast, prostate and other solid tumours (reviewed in [ 7 ]). However, DOT1L inhibitors use in clinics is still hampered by low tolerance and severe side effects caused by drug administration indicating to the need of therapeutic efficacy improvement for these epigenetic drugs [ 7 ]. Therefore, new therapies are being sought to allow the doses of DOT1L-targeting drugs to be reduced, including application of drug combination treatments.…”