Authors
Jianyong Liu, Qing-Li He, Jianya Zhou, Ajay M Vaghasia, Roshan Chikarmane, Glenn Hauk, Archana Rachakonda, Nicole Castagna, Ruchama C Steinberg, Minh-Tam Pham, Jordan M Gregg, Alok Mishra, Yuhan Yang, Talha Anwar, Roy Elias, Pengshan Li, Jasmine Yun-Tong Kung, Anthony C O'Donnell, Nicole M Anders, Teresia M Wanjiku, Philipp Nuhn, Joong Sup Shim, Hugh Giovinazzo, David M Esopi, Kunhwa Kim, Jonathan Coulter, Rulin Wang, Jianying Zhou, Michelle A Rudek, Kathleen Gabrielson, Angelo M De Marzo, James M Berger, Jun O Liu, William G Nelson, Srinivasan Yegnasubramanian
Published in
Nature communications. Volume 17. Issue 1. Aug 26, 2026. Epub Aug 26, 2026.
Abstract
Abnormal DNA hypermethylation mediated by DNA methyltransferases (DNMT) is a nearly universal hallmark of human cancers. However, while DNA methyltransferase inhibitors (DNMTi) such as decitabine and azacitidine are effective in treating myelodysplatic syndrome/leukemia, they have had limited utility for the majority of other cancers. Through a chemical library screen, we identify that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, and multiple of its analogs, significantly augment the epigenetic and anti-cancer effects of decitabine in vitro and in vivo. These effects are attributable to inhibition of DCTPP1-mediated cleavage of 5-aza-deoxycytidine triphosphate, the convergent activated metabolite of nucleoside DNMTi, leading to enhanced drug incorporation into genomic DNA, increased DNMT degradation, enhanced DNA demethylation and associated transcriptional reprogramming. We show that high DCTPP1 expression mediates cell-intrinsic resistance to nucleoside DNMTi, and that triptolide and its analogs could overcome this resistance. These findings nominate combining DNMTi with triptolide or its analogs as a rational cancer therapeutic strategy.
PMID:
42802274
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.
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