Hexokinase 2 is a transcriptional target and regulator of the aromatic hydrocarbon receptor (AhR) signaling network

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Hexokinase 2 (HK2) catalyzes the phosphorylation of glucose to glucose-6-phosphate, the first irreversible step in glycolysis. In addition, the enzyme can also regulate the function and activity of cellular and nuclear proteins, such as transcription factors and mitochondrial proteins important for cell survival. The description of the diverse functions of HK2 in the cell remains a source of many studies.
The publication led by the team "Epigenetics, DNA Replication and Cancer" with the help of two teams of Université Paris Cité, "Metatox" and "Metabolism, Pharmacochemistry and Neurochemistry" describes the function of HK2 in the regulation of the AHR (aromatic hydrocarbon receptor) signaling pathway. AHR is a transcription factor capable of binding many ligands. Historically, AHR is a key component of the transcriptional response to environmental pollutants, but it is also involved in many normal physiological processes and has been shown to be a major player in cancer. In this study, the team shows that HK2 is not only a transcriptional target of AHR, but also a positive regulator of the activity of the signaling pathway in response to different AHR ligands. This new HK2/AHR axis could play a key role in many cancers and represent a possible new therapeutic target.

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Hexokinase 2 (HK2) and the aromatic hydrocarbon receptor (AHR) are two major players in cancer. The function of HK2 in cancer has been associated for many years with its ability to phosphorylate glucose and to promote numerous metabolic pathways essential for tumor growth, dissemination of cancer cells and resistance to chemotherapies. The function of AHR is more complex and it is able to play a pro- or anti-tumor role. These different roles could be related to the effect of the environment on the expression of AHR as well as on its transcriptional activity. Indeed, AHR is a transcription factor activated by different ligands, often environmental pollutants, such as dioxin or benzo(a)pyrene.

In this work, the team shows that AHR binds to the HK2 gene in different cell types and that in response to the exposure of cells to different ligands of AHR the expression of HK2 is increased at the transcriptional and protein level. HK2 expression is thus directly regulated by AHR and its ligands. Notably, the amplitude of this transcriptional response differs according to the cell types and the AHR ligands tested. These data highlight the variability of cellular responses to the activation of the AHR signaling pathway.

In a second step, the team shows that the expression level of HK2 modulates the activity of the AHR signaling pathway in a context-specific manner. The effect of HK2 overexpression is due, in part, to the regulation of AHR expression itself, in one of the cell types studied. In this cell model, the increase in AHR expression is associated with a change in the activity of the gene promoter, including a loss of DNA methylation, a transcriptional inhibitory mark.

Proposed model of the HK2/AHR axis Proposed model of the HK2/AHR axis. Overexpression of HK2 increases the activity of the AHR signaling pathway and one of the mode of action described is the regulation of DNA methylation at the AHR promoter by HK2.

Finally, using molecular and clinical data from patients with 33 types of cancers, the team shows that HK2 expression and AHR promoter methylation could be used as prognostic markers for several cancers, such as prostate, pancreatic and glioma.

In sum, the study reports an unexpected relationship between a glycolysis enzyme, HK2, and a transcription factor, AHR, in cancer.

 

This work was made possible thanks to the financial support of the Laboratory of Excellence "Who am I?", the Foundation for Medical Research, the Cancer Plan (2014-2019), the Groupement des Entreprises Ile-de-France contre le Cancer (GEFLUC) and the Ligue Régionale Contre le Cancer Ile-de-France.

 

Reference

Hexokinase 2 is a transcriptional target and a positive modulator of AHR signaling. Manon Watzky, Solene Huard, Ludmila Juricek, Julien Dairou, Caroline Chauvet, Xavier Coumoul, Anne Letessier, and Benoit Miotto.  Nucleic Acids Research, 2022,  May 24;gkac360.  doi: 10.1093/nar/gkac360. Online ahead of print.

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Benoit Miotto

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Anne Letessier

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