Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L-formate axis

doi:10.1111/jpi.12767

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/23504

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/23504

Title:	Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L-formate axis
Authors:	Cui, L;Zhao, XY;Jin, ZN;Wang, HL;Yang, SF;Hu, S
Keywords:	formate;HNSCC;melatonin;metabolomics;MTHFD1L
Date:	2021
Issue Date:	2022-08-05T09:38:21Z (UTC)
Publisher:	WILEY
ISSN:	0742-3098
Abstract:	Metabolic remodeling is now widely recognized as a hallmark of cancer, yet its role in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. In this study, metabolomic analysis of melatonin-treated HNSCC cell lines revealed that exogenous melatonin inhibited many important metabolic pathways including folate cycle in HNSCC cells. Methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L), a metabolic enzyme of the folate cycle regulating the production of formate, was identified as a downstream target of melatonin. MTHFD1L was found to be markedly upregulated in HNSCC, and MTHFD1L overexpression was significantly associated with unfavorable clinical outcome of HNSCC patients. In addition, MTHFD1L promoted HNSCC progression in vitro and in vivo and reversed the oncostatic effects of exogenous melatonin. More importantly, the malignant phenotypes suppressed by knockdown of MTHFD1L or exogenous melatonin could be partially rescued by formate. Furthermore, we found that melatonin inhibited the expression of MTHFD1L in HNSCC cells through the downregulation of cyclic AMP-responsive element-binding protein 1 (CREB1) phosphorylation. Lastly, this novel regulatory axis of melatonin-p-CREB1-MTHFD1L-formate was also verified in HNSCC tissues. Collectively, our findings have demonstrated that MTHFD1L-formate axis promotes HNSCC progression and melatonin inhibits HNSCC progression through CREB1-mediated downregulation of MTHFD1L and formate. These findings have revealed new metabolic mechanisms in HNSCC and may provide novel insights on the therapeutic intervention of HNSCC.
URI:	http://dx.doi.org/10.1111/jpi.12767 https://www.webofscience.com/wos/woscc/full-record/WOS:000702753400001 https://ir.csmu.edu.tw:8080/handle/310902500/23504
Relation:	JOURNAL OF PINEAL RESEARCH ,2021,v71,issue 4
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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