NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma

Jin, Xiaoye; Lou, Xiayuan; Qi, Haoxiang; Zheng, Chao; Li, Bo; Siwu, Xuerong; Liu, Ren; Lv, Qiaoli; Zhao, An; Ruan, Jian; Jiang, Ming

doi:10.1038/s41389-024-00536-z

Oncogenesis

2024

DOI: 10.1038/s41389-024-00536-z

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NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma

Xiaoye Jin,

Xiayuan Lou,

Haoxiang Qi

et al.

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Disease-associated programming of cell memory in glycogen storage disorder type 1a

Sprecher

Dsouza

Mishra

et al. 2023

Preprint

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Glycogen storage disorder type 1a (GSD1a) is caused by loss-of-function mutations in the catalytic subunit of glucose-6-phosphatase enzyme (G6PC1) in the liver, kidney and intestine exclusively. Here we show the surprising results that while not expressing G6PC1, primary skin fibroblasts isolated from GSD1a patients skin biopsies preserve a distinctive disease phenotype irrespective of the different culture conditions under which they grow. This discovery was initially made by phenotypic image-based high content analysis (HCA). Deeper analysis into this disease phenotype, revealed impaired lysosomal and mitochondrial functions in GSD1a cells, which were driven by a transcriptional dysregulation of the NAD+/NADH-Sirt1-TFEB regulatory axis. This dysregulation impacts the normal balance between mitochondrial biogenesis and mitophagy in the patients cells. The distinctive GSD1a fibroblasts phenotype involves elevated H3 K27 histone acetylation and global DNA hypomethylation suggesting that in some way the disease imprinted a distinctive cell phenotype in these cells. Remarkably, GHF201, an established glycogen reducing molecule, which ameliorated GSD1a pathology in a liver-targeted inducible L.G6pc-/- knockout mouse model, also reversed impaired cellular functions in GSD1a patients fibroblasts. Altogether, this experimental evidence strongly suggests that these cells express a strong and reversible disease phenotype without expressing the causal G6PC1 gene.

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Disease-associated programming of cell memory in glycogen storage disorder type 1a

Sprecher

Dsouza

Mishra

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

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NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma

Cited by 1 publication

References 67 publications

Disease-associated programming of cell memory in glycogen storage disorder type 1a

Disease-associated programming of cell memory in glycogen storage disorder type 1a

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