Chemical catalyst manipulating cancer epigenome and transcription

Yuki Yamanashi, Shinpei Takamaru, Atsushi Okabe, Satoshi Kaito, Yuto Azumaya, Yugo R. Kamimura, Kenzo Yamatsugu, Tomoya Kujirai, Hitoshi Kurumizaka, Atsushi Iwama, Atsushi Kaneda, Shigehiro A. Kawashima () and Motomu Kanai ()
Additional contact information
Yuki Yamanashi: The University of Tokyo
Shinpei Takamaru: The University of Tokyo
Atsushi Okabe: Chiba University
Satoshi Kaito: The University of Tokyo
Yuto Azumaya: The University of Tokyo
Yugo R. Kamimura: The University of Tokyo
Kenzo Yamatsugu: The University of Tokyo
Tomoya Kujirai: The University of Tokyo
Hitoshi Kurumizaka: The University of Tokyo
Atsushi Iwama: The University of Tokyo
Atsushi Kaneda: Chiba University
Shigehiro A. Kawashima: The University of Tokyo
Motomu Kanai: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The number and variety of identified histone post-translational modifications (PTMs) are continually increasing. However, the specific consequences of each histone PTM remain largely unclear, primarily due to the lack of methods for selectively and rapidly introducing a desired histone PTM in living cells without genetic engineering. Here, we report the development of a cell-permeable histone acetylation catalyst, BAHA-LANA-PEG-CPP44, which selectively enters leukemia cells, binds to chromatin, and acetylates H2BK120 of endogenous histones in a short reaction time. Time-course analyses of this in-cell catalytic reaction revealed that H2BK120 acetylation attenuates the chromatin binding of negative elongation factor E (NELFE), an onco-transcription factor. This H2BK120 acetylation-mediated removal of NELFE from chromatin reshapes transcription, slows leukemia cell viability, and reduces their tumorigenic potential in mice. Therefore, this histone acetylation catalyst provides a unique tool for elucidating the time-resolved consequences of histone PTMs and may offer a modality for cancer chemotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-56204-2

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