Nur Suza Mohammad, Shait Mohammed Mohammed Razeeth, Zamzami Mazin A, Choudhry Hani, Ahmad Aamir, Ateeq Bushra, Rather Irfan A, Khan Mohammad Imran
Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Centre of Artificial Intelligence for Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Metabolites. 2022 Mar 21;12(3):267. doi: 10.3390/metabo12030267.
Tumor cells detached from the extracellular matrix (ECM) undergo anoikis resistance and metabolic reprogramming to facilitate cancer cell survival and promote metastasis. During ECM detachment, cancer cells utilize genomic methylation to regulate transcriptional events. One-carbon (1C) metabolism is a well-known contributor of SAM, a global substrate for methylation reactions, especially DNA methylation. DNA methylation-mediated repression of NK cell ligands MICA and MICB during ECM detachment has been overlooked. In the current work, we quantitated the impact of ECM detachment on one-carbon metabolites, expression of 1C regulatory pathway genes, and total methylation levels. Our results showed that ECM detachment promotes the accumulation of one-carbon metabolites and induces regulatory pathway genes and total DNA methylation. Furthermore, we measured the expression of well-known targets of DNA methylation in NK cell ligands in cancer cells, namely, MICA/B, during ECM detachment and observed low expression compared to ECM-attached cancer cells. Finally, we treated the ECM-detached cancer cells with vitamin C (a global methylation inhibitor) and observed a reduction in the promoter methylation of NK cell ligands, resulting in MICA/B re-expression. Treatment with vitamin C was also found to reduce global DNA methylation levels in ECM-detached cancer cells.
从细胞外基质（ECM）脱离的肿瘤细胞会产生失巢凋亡抗性和代谢重编程，以促进癌细胞存活并促进转移。在ECM脱离过程中，癌细胞利用基因组甲基化来调节转录事件。一碳（1C）代谢是S-腺苷甲硫氨酸（SAM）的一个众所周知的来源，SAM是甲基化反应（尤其是DNA甲基化）的一种通用底物。在ECM脱离过程中，DNA甲基化介导的自然杀伤（NK）细胞配体MICA和MICB的抑制作用一直被忽视。在当前的研究中，我们定量了ECM脱离对一碳代谢物、1C调节途径基因表达和总甲基化水平的影响。我们的结果表明，ECM脱离促进了一碳代谢物的积累，并诱导了调节途径基因和总DNA甲基化。此外，我们测量了癌细胞中NK细胞配体中众所周知的DNA甲基化靶点，即MICA/B，在ECM脱离过程中的表达，并观察到与附着于ECM的癌细胞相比其表达较低。最后，我们用维生素C（一种通用甲基化抑制剂）处理ECM脱离的癌细胞，观察到NK细胞配体的启动子甲基化减少，导致MICA/B重新表达。还发现用维生素C处理可降低ECM脱离的癌细胞中的总DNA甲基化水平。
