5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion

Abstract

Nonsense-mediated RNA decay (NMD) is an RNA-based quality control mechanism that eliminates transcripts bearing premature translation termination codons (PTC). Approximately, one-third of all inherited disorders and some forms of cancer are caused by nonsense or frame shift mutations that introduce PTCs, and NMD can modulate the clinical phenotype of these diseases. 5-azacytidine is an analogue of the naturally occurring pyrimidine nucleoside cytidine, which is approved for the treatment of myelodysplastic syndrome and myeloid leukemia. Here, we reveal that 5-azacytidine inhibits NMD in a dose-dependent fashion specifically upregulating the expression of both PTC-containing mutant and cellular NMD targets. Moreover, this activity of 5-azacytidine depends on the induction of MYC expression, thus providing a link between the effect of this drug and one of the key cellular pathways that are known to affect NMD activity. Furthermore, the effective concentration of 5-azacytidine in cells corresponds to drug levels used in patients, qualifying 5-azacytidine as a candidate drug that could potentially be repurposed for the treatment of Mendelian and acquired genetic diseases that are caused by PTC mutations.

DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats

“…This would be of upmost importance for those cancer types with low mutational burden that respond poorly to immune therapy 43 . The here described mechanism likely synergizes with other effects of epigenetic therapy, including the inhibition of NMD 44 , transcription of viral defense genes 4 , increased antigen processing and presentation 45 , re-expression of epigenetically silenced inflammatory chemokines 46 , and up-regulation of CTAs 47 . Future proteomic approaches combined with T-cell cytotoxicity assays will further shed light on the interaction between epigenetic and immune therapy and the role of ERV-derived antigen presentation.…”

Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia

“…Detailed studies in clinical trial cohorts are needed to delineate the impact of HMAs in TET2 -mutant AML and AG-221 in IDH2 -mutant AML on mutational burden and clonal structure, and to determine if mutant cells can persist in a clonal, non-leukemic state in the setting of epigenetic therapies which induce differentiation of leukemia cells. Furthermore, although we observe a change in methylation with 5-azacytidine, its effect on RNA biology may also play a role in response (43, 44). Similarly, IDH2 inhibitors may affect other α-ketoglutarate dependent enzymes beyond TET2 and its effects on DNA methylation that may alter treatment response (45).…”

Nonsense-mediated mRNA decay in humans at a glance

“…In contrast to Ataluren, cardiac glycosides, which elevate the level of intracellular Ca 2+ , are capable of inhibiting NMD at concentrations that reportedly do not affect cellular viability (Nickless et al, 2014). It might be possible to concomitantly use Ataluren and cardiac glycosides, or possibly a clinically effective nonsense suppressor with either another small reagent that has been reported to inhibit NMD (Bhuvanagiri et al, 2014;Martin et al, 2014;Dang et al, 2009;Feng et al, 2015;Gopalsamy et al, 2012;Usuki et al, 2004) or one or more antisense oligonucleotides that occlude deposition of the one or more EJCs that would normally reside downstream of a particular PTC (Nomakuchi et al, in press). Another approach that might be worthwhile for obtaining full-length protein from diseaseassociated mRNAs is site-directed pseudouridylation of in-frame PTCs (Karijolich and Yu, 2011); by providing a gene-specific therapeutic strategy, such a strategy would be expected to have only minimal toxic side effects.…”