A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition
Abstract UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase, and is frequently mutated in various types of human cancers. Although UTX appears to play a crucial role in oncogenesis, the mechanisms involved are still largely unknown. Here we show that a specific pharmacological inhibi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-83857-y |
| _version_ | 1831631128260247552 |
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| author | Shojiro Kitajima Wendi Sun Kian Leong Lee Jolene Caifeng Ho Seiichi Oyadomari Takashi Okamoto Hisao Masai Lorenz Poellinger Hiroyuki Kato |
| author_facet | Shojiro Kitajima Wendi Sun Kian Leong Lee Jolene Caifeng Ho Seiichi Oyadomari Takashi Okamoto Hisao Masai Lorenz Poellinger Hiroyuki Kato |
| author_sort | Shojiro Kitajima |
| collection | DOAJ |
| description | Abstract UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase, and is frequently mutated in various types of human cancers. Although UTX appears to play a crucial role in oncogenesis, the mechanisms involved are still largely unknown. Here we show that a specific pharmacological inhibitor of H3K27 demethylases, GSK-J4, induces the expression of transcription activating factor 4 (ATF4) protein as well as the ATF4 target genes (e.g. PCK2, CHOP, REDD1, CHAC1 and TRIB3). ATF4 induction by GSK-J4 was due to neither transcriptional nor post-translational regulation. In support of this view, the ATF4 induction was almost exclusively dependent on the heme-regulated eIF2α kinase (HRI) in mouse embryonic fibroblasts (MEFs). Gene expression profiles with UTX disruption by CRISPR-Cas9 editing and the following stable re-expression of UTX showed that UTX specifically suppresses the expression of the ATF4 target genes, suggesting that UTX inhibition is at least partially responsible for the ATF4 induction. Apoptosis induction by GSK-J4 was partially and cell-type specifically correlated with the activation of ATF4-CHOP. These findings highlight that the anti-cancer drug candidate GSK-J4 strongly induces ATF4 and its target genes via HRI activation and raise a possibility that UTX might modulate cancer formation by regulating the HRI-ATF4 axis. |
| first_indexed | 2024-12-19T04:54:44Z |
| format | Article |
| id | doaj.art-269f3fc324ab4ebb93a68e6e694339e8 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:54:44Z |
| publishDate | 2021-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-269f3fc324ab4ebb93a68e6e694339e82022-12-21T20:35:15ZengNature PortfolioScientific Reports2045-23222021-02-0111111410.1038/s41598-021-83857-yA KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibitionShojiro Kitajima0Wendi Sun1Kian Leong Lee2Jolene Caifeng Ho3Seiichi Oyadomari4Takashi Okamoto5Hisao Masai6Lorenz Poellinger7Hiroyuki Kato8Cancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeInstitute of Advanced Medical Sciences, Tokushima UniversityDepartment of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical ScienceGenome Dynamics Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical ScienceCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeAbstract UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase, and is frequently mutated in various types of human cancers. Although UTX appears to play a crucial role in oncogenesis, the mechanisms involved are still largely unknown. Here we show that a specific pharmacological inhibitor of H3K27 demethylases, GSK-J4, induces the expression of transcription activating factor 4 (ATF4) protein as well as the ATF4 target genes (e.g. PCK2, CHOP, REDD1, CHAC1 and TRIB3). ATF4 induction by GSK-J4 was due to neither transcriptional nor post-translational regulation. In support of this view, the ATF4 induction was almost exclusively dependent on the heme-regulated eIF2α kinase (HRI) in mouse embryonic fibroblasts (MEFs). Gene expression profiles with UTX disruption by CRISPR-Cas9 editing and the following stable re-expression of UTX showed that UTX specifically suppresses the expression of the ATF4 target genes, suggesting that UTX inhibition is at least partially responsible for the ATF4 induction. Apoptosis induction by GSK-J4 was partially and cell-type specifically correlated with the activation of ATF4-CHOP. These findings highlight that the anti-cancer drug candidate GSK-J4 strongly induces ATF4 and its target genes via HRI activation and raise a possibility that UTX might modulate cancer formation by regulating the HRI-ATF4 axis.https://doi.org/10.1038/s41598-021-83857-y |
| spellingShingle | Shojiro Kitajima Wendi Sun Kian Leong Lee Jolene Caifeng Ho Seiichi Oyadomari Takashi Okamoto Hisao Masai Lorenz Poellinger Hiroyuki Kato A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition Scientific Reports |
| title | A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition |
| title_full | A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition |
| title_fullStr | A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition |
| title_full_unstemmed | A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition |
| title_short | A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition |
| title_sort | kdm6 inhibitor potently induces atf4 and its target gene expression through hri activation and by utx inhibition |
| url | https://doi.org/10.1038/s41598-021-83857-y |
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