What question did this study set out to answer?

To investigate how the carbocyclic antimetabolite cAzadC affects TET enzyme expression and hydroxymethylcytosine levels in aggressive cancers.

April 1, 2026Open Access

Increasing TET expression and 5-hydroxymethylcytosine formation by a carbocyclic 5-aza-2'-deoxy-cytidine antimetabolite

Puntos clave

To investigate how the carbocyclic antimetabolite cAzadC affects TET enzyme expression and hydroxymethylcytosine levels in aggressive cancers.
Utilized patient-derived xenograft models of acute myeloid leukemia (AML) for in vivo testing.
Administered the carbocyclic antimetabolite 5-aza-2'-deoxycytidine (cAzadC) to assess its impact on TET expression.
Measured levels of 5-hydroxymethylcytosine post-treatment to evaluate epigenetic changes.
cAzadC significantly increased TET2 expression in cancer models.
Treatment led to a marked rise in 5-hydroxymethylcytosine levels.
Enhanced anti-cancer effects were observed in vivo, indicating reactivation of cellular anti-tumor responses.

Resumen

Abstract Ten-eleven translocation (TET) enzymes are critical epigenetic regulators, which oxidize the methylated cytosine nucleobase 5-methyl-dC (5mdC) in the genome to 5-hydroxymethyl-dC (5hmdC) in an α-ketoglutarate-dependent manner. Because the presence of 5mdC in the promoter region of a given gene silences its expression, this oxidation goes in hand with the reactivation of such silenced genes. In different highly aggressive cancers such as acute myeloid leukemia (AML) and glioblastoma, loss of TET enzyme function and therefore reduced 5hmdC levels pave the way for tumor development. Impairment of TET activity can occur through metabolic inhibition, through loss-of-function mutations in TET genes themselves, and finally through suppression of TET-expression via epigenetic silencing. Reactivation of TET enzyme expression represents a major aim of epigenetic cancer therapy. Here we show that the carbocyclic antimetabolite 5-aza-2’deoxycytidine (cAzadC), which is supposed to suppress the methylation of DNA during replication, leads to a substantial increase of TET2 expression and strongly increasing 5hmdC levels. We show that the treatment with cAzadC goes in hand with the broad reactivation of the cellular anti-tumor responses. With patient-derived xenograft AML-mouse models, we show that this translates into a strongly improved anti-cancer effect in vivo. Acknowledgements We thank the Deutsche Forschungsgemeinschaft (DFG) for financial support for this project via CRC1309 (Grant Nr.325871075, Projects A04 (TC), A05 (JW) and C08 (FRT)), CRC1361 (Grant Nr. 393547839, Project 2 (TC)), TRR237 (Grant Nr.369799452, Project A27 (TC)). Further support is acknowledged from the BMBF in the framework of the Zukunftsclusterprogram (Cluster for Nucleic Acid Therapeutics Munich, CNATM) (Project ID: 03ZU1201AA (FRT, IJ and TC)). FRT thanks theDaimler und Benz Stiftung (Grant Nr. 32-09/21) and the Fonds der Chemischen Industrie (Liebig Fellowship Li 210/06) forsupport. This project has received funding from the European Research Council (ERC) under the European Union's Horizon2020 research and innovation program under grant agreement Nr. 741912 (EPiR) (TC), the Marie Sklodowska-Curie grantagreements Nr. 861381 (EP) and Nr. 101072780 (DG). MD thanks the Fonds der Chemischen Industrie for a PhD fellowship.YVG was supported by the Bavarian Graduate program RNAmed. IJ thanks German Cancer Aid for support via a MildredScheel Professorship. The authors thank Markus Müller for critical discussions and help with manuscript preparation.Keywords : Epigenetics, DNA methylation, DNMT inhibition, DNA hydroxymethylation, Acute myeloid leukemia, Decitabine

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