Chemical catalyst manipulating cancer epigenome and transcription
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56204-2 |
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| author | 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 Motomu Kanai |
| author_facet | 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 Motomu Kanai |
| author_sort | Yuki Yamanashi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e2b469f36b874443823ef6f70f111df5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e2b469f36b874443823ef6f70f111df52025-01-26T12:40:34ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56204-2Chemical catalyst manipulating cancer epigenome and transcriptionYuki Yamanashi0Shinpei Takamaru1Atsushi Okabe2Satoshi Kaito3Yuto Azumaya4Yugo R. Kamimura5Kenzo Yamatsugu6Tomoya Kujirai7Hitoshi Kurumizaka8Atsushi Iwama9Atsushi Kaneda10Shigehiro A. Kawashima11Motomu Kanai12Graduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoDepartment of Molecular Oncology, Graduate School of Medicine, Chiba UniversityDivision of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoInstitute for Quantitative Biosciences, The University of TokyoInstitute for Quantitative Biosciences, The University of TokyoDivision of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of TokyoDepartment of Molecular Oncology, Graduate School of Medicine, Chiba UniversityGraduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoAbstract 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.https://doi.org/10.1038/s41467-025-56204-2 |
| spellingShingle | 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 Motomu Kanai Chemical catalyst manipulating cancer epigenome and transcription Nature Communications |
| title | Chemical catalyst manipulating cancer epigenome and transcription |
| title_full | Chemical catalyst manipulating cancer epigenome and transcription |
| title_fullStr | Chemical catalyst manipulating cancer epigenome and transcription |
| title_full_unstemmed | Chemical catalyst manipulating cancer epigenome and transcription |
| title_short | Chemical catalyst manipulating cancer epigenome and transcription |
| title_sort | chemical catalyst manipulating cancer epigenome and transcription |
| url | https://doi.org/10.1038/s41467-025-56204-2 |
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