Theranostics 2021; 11(11):5232-5247. doi:10.7150/thno.53417 This issue Cite
Research Paper
1. Graduate Program of Medical Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
2. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
3. Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
4. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
5. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
6. Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
7. Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan.
8. Department of Cosmetology and Health Care, Min-Hwei College of Health Care Management, Tainan, Taiwan.
9. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.
10. Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
11. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear.
Methods: The protein expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition in vitro and in vivo. The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2.
Results: NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC.
Conclusions: Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer.
Keywords: Nuclear factor erythroid 2-related factor 2 (NRF2), head and neck squamous cell carcinoma (HNSCC), c-MYC, pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT)