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Can Combined EZH2 Inhibition and TET2/DNMT3A Targeted Therapeutics Fight Back Against Cancer-associated Chromatin Condensation?
June 24, 2026
Table of Contents:
A Deeper Epigenetic Understanding of Cancer Treatment and Recurrence
The Enhancer of zeste homolog 1 and 2 (EZH1 and 2) H3K27me3-specific methyltransferases help to support the stable regulation of the histone methylation patterns that underpin the gene expression profiles of normal cells (Margueron et al., Shen et al., and Yamagishi et al.). The cancer-associated excessive deposition of the repressive histone modification H3K27me3 at gene promoters, driven by aberrant increases in EZH2 expression, leads to increased chromatin compaction/condensation and the expression of a pro-tumorigenic gene expression profile characterized by a lack of tumor suppressor gene expression (Margueron & Reinberg, Yamagishi & Uchimaru, and Bhat et al.).
As such, multiple studies have highlighted the therapeutic utility of EZH1/2 co-inhibition by exposure to the potent and selective small molecule valemetostat in leukemia/lymphoma patients (Morishima et al. and Izutsu et al.); however, we lacked a deep understanding of the exact mechanisms by which such H3K27me3-targeted therapies successful affected tumor cells at the epigenetic level and the epigenetic pathways underpinning reported clinical recurrence after long periods of treatment exposure. Do cancer cells employ another epigenetic mechanism to overcome EZH1/2 co-inhibition and reinstate a pro-tumorigenic condensed chromatin landscape in patient tumor cells?
To this end, researchers led by Makoto Yamagishi, Yutaka Suzuki, and Kaoru Uchimaru (The University of Tokyo) explored these epigenetic “loose ends” in patients with adult T cell leukemia/lymphoma - a rare type of T cell lymphoma with poor prognosis (Katsuya et al. and Cook et al.) renowned for increased H3K27me3 levels (Yamagishi et al. and Fujikawa et al.) – that had undergone long-term treatment with valemetostat.
In their recent Nature study, Yamagishi and Kuze et al. now report the association of positive clinical responses with reduced levels of H3K27me3-associated chromatin condensation localized to gene promoters; however, they also linked disease recurrence to chromatin recondensation via an increase in de novo DNA methylation thanks to mutations in the TET2 gene or elevated levels of DNA (cytosine-5)-methyltransferase 3A (DNMT3A). The TET methylcytosine dioxygenase proteins (TET1-3) regulate gene expression by promoting DNA demethylation and creating a permissive chromatin landscape (Zhang et al.), while DNMT3A is responsible for de novo DNA methylation. Overall, the authors believe that these data could pave the way for the development of combination epigenetic strategies targeting histone and DNA methylation to counteract chromatin condensation, cancer development, and treatment-associated recurrence.
EZH2 Inhibition Robustly Impacts Cancer; TET2 Mutations and DNMT3A Overexpression Lead the Fightback
Overall, the authors of this fascinating study integrated multi-omics analyses and clinical data to demonstrate that treatment with the EZH1/2 inhibitor valemetostat reduced tumor burden and induced durable clinical responses in patients with aggressive lymphomas harboring multiple genetic mutations by reversing chromatin condensation and reducing H3K27me3 levels at loci encompassing tumor suppressor genes. Analyses employed throughout the study included bulk and single-cell RNA-seq, bulk and single-cell ChIP-seq, single-cell ATAC-seq, and DNA methylation profiling. Overall, the initial findings linked clinical improvements to the valemetostat-induced restoration of the tumor cell epigenome toward a healthy state.
However, the team behind this research also discovered that long-term valemetostat treatment led to the emergence of tumor cells with chromatin condensation patterns similar to those observed in untreated patients, which suggested the indispensable role of chromatin compaction in tumor maintenance/growth and underscored the perhaps limited pathways available to treated cancer cells to escape the influence of valemetostat.
While the emergence of mutations in the EZH2 gene that affected the interaction of the H3K27me3 methyltransferase protein with valemetostat (or in epigenetic factors with cooperative roles in gene silencing) explained some of these resistant tumor cells, the authors discovered that TET2 mutations (which lead to reduced levels of DNA demethylation) or elevated DNMT3A expression (which leads to increased levels of DNA methylation) could re-induce chromatin condensation in other tumor cells through increased DNA methylation levels at the previously H3K27me3-associated regions. Overall, these data implicate chromatin condensation through two distinct mechanisms – EZH2-mediated H3K27me3 deposition and increased DNA methylation – to tumor initiation/growth and regrowth after acquiring resistance.
Combined EZH2 Inhibition and TET2/DNMT3A Targeted Therapeutics: The Way Forward for Cancer Treatment?
Overall, this study of the molecular and cellular dynamics in adult T cell leukemia/lymphoma patients treated with the EZH2 inhibitor valemetostat, which integrated multiomics analyses with clinical resources, revealed the importance of chromatin condensation in the development and recurrence of cancer and also underscored the significant potential of combining epigenetic modalities as an effective treatment strategy. Could long-term treatment with valemetostat in combination with TET2/DNMT3A targeted therapeutics lead to enduring tumor remission in patients with aggressive cancers?
Of note, the authors of this exciting study employed a range of services (chromatin immunoprecipitation experiments and analyses) and products (antibodies against H3K27me3, H3K27ac, and SUZ12) from Active Motif; additional relevant products include TET antibodies and recombinant proteins. How can Active Motif help your cancer epigenetics study?
About the author
Stuart P. Atkinson, Ph.D.
Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!
Contact Stuart on X with any questions
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