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Updated: Nov 16, 2025
In vivo Application of the REMOTE-control System for the Manipulation of Endogenous Gene Expression
Published on: March 29, 2019
A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition
Shojiro Kitajima1,2, Wendi Sun1, Kian Leong Lee1,3
1Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
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.
Insights
The anti-cancer drug GSK-J4 activates the HRI-ATF4 pathway, inducing cancer-related genes. UTX (KDM6A) normally suppresses these genes, suggesting its role in cancer by regulating this axis.
Area of Science:
- Molecular Biology
- Cancer Biology
- Epigenetics
Background:
- UTX/KDM6A is a key histone demethylase involved in human cancers.
- The precise mechanisms of UTX in oncogenesis remain unclear.
- Targeting histone demethylases is a promising cancer therapy strategy.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the effects of the H3K27 demethylase inhibitor GSK-J4.
- To elucidate the role of UTX in regulating the ATF4 pathway.
- To explore the potential of targeting the HRI-ATF4 axis in cancer treatment.
Main Methods:
- Utilized GSK-J4, a specific H3K27 demethylase inhibitor.
- Employed CRISPR-Cas9 gene editing to disrupt UTX.
- Analyzed gene expression profiles and protein levels of ATF4 and its targets.
- Investigated the role of heme-regulated eIF2α kinase (HRI) in ATF4 induction.
Main Results:
- GSK-J4 treatment robustly induced transcription activating factor 4 (ATF4) and its target genes.
- ATF4 induction by GSK-J4 was primarily dependent on HRI activation.
- UTX disruption led to increased expression of ATF4 target genes, indicating UTX suppresses them.
- GSK-J4 induced apoptosis, partially correlated with ATF4-CHOP activation.
Conclusions:
- The anti-cancer drug candidate GSK-J4 induces ATF4 and target genes via HRI activation.
- UTX may influence cancer development by modulating the HRI-ATF4 signaling pathway.
- Targeting the HRI-ATF4 axis presents a potential therapeutic strategy in cancers with altered UTX function.
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