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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Autores principales:	Shojiro Kitajima, Wendi Sun, Kian Leong Lee, Jolene Caifeng Ho, Seiichi Oyadomari, Takashi Okamoto, Hisao Masai, Lorenz Poellinger, Hiroyuki Kato
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/269f3fc324ab4ebb93a68e6e694339e8
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spelling	oai:doaj.org-article:269f3fc324ab4ebb93a68e6e694339e82021-12-02T11:37:27ZA KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition10.1038/s41598-021-83857-y2045-2322https://doaj.org/article/269f3fc324ab4ebb93a68e6e694339e82021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83857-yhttps://doaj.org/toc/2045-2322Abstract 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.Shojiro KitajimaWendi SunKian Leong LeeJolene Caifeng HoSeiichi OyadomariTakashi OkamotoHisao MasaiLorenz PoellingerHiroyuki KatoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	kdm6 inhibitor potently induces atf4 and its target gene expression through hri activation and by utx inhibition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/269f3fc324ab4ebb93a68e6e694339e8
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A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition

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