Cui Li, Zhao Xinyuan, Jin Zhenning, Wang Hailin, Yang Shun-Fa, Hu Shen
School of Dentistry, University of California, Los Angeles, California, USA.
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.
J Pineal Res. 2021 Dec;71(4):e12767. doi: 10.1111/jpi.12767. Epub 2021 Oct 2.
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.
代谢重塑如今已被广泛认为是癌症的一个标志，但其在头颈部鳞状细胞癌（HNSCC）中的作用在很大程度上仍不清楚。在本研究中，对褪黑素处理的HNSCC细胞系进行代谢组学分析发现，外源性褪黑素抑制了许多重要的代谢途径，包括HNSCC细胞中的叶酸循环。亚甲基四氢叶酸脱氢酶1样蛋白（MTHFD1L）是叶酸循环中调节甲酸生成的一种代谢酶，被确定为褪黑素的下游靶点。研究发现MTHFD1L在HNSCC中显著上调，且MTHFD1L的过表达与HNSCC患者不良的临床结局显著相关。此外，MTHFD1L在体外和体内均促进HNSCC进展，并逆转了外源性褪黑素的抑癌作用。更重要的是，敲低MTHFD1L或外源性褪黑素所抑制的恶性表型可被甲酸部分挽救。此外，我们发现褪黑素通过下调环磷酸腺苷反应元件结合蛋白1（CREB1）的磷酸化来抑制HNSCC细胞中MTHFD1L的表达。最后，这种褪黑素-p-CREB1-MTHFD1L-甲酸的新型调控轴在HNSCC组织中也得到了验证。总的来说，我们的研究结果表明，MTHFD1L-甲酸轴促进HNSCC进展，而褪黑素通过CREB1介导的MTHFD1L和甲酸下调来抑制HNSCC进展。这些发现揭示了HNSCC新的代谢机制，并可能为HNSCC的治疗干预提供新的见解。
