Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USA.
Genes (Basel). 2023 Sep 19;14(9):1818. doi: 10.3390/genes14091818.
Previous studies have shown that inhibition of TNF family member FN14 (gene: ) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development.
先前的研究表明，在结肠肿瘤中抑制 TNF 家族成员 FN14（基因：）可减少炎症细胞因子的表达，并减轻癌症引起的恶病质。然而，FN14 表达调控的分子机制仍不清楚。肿瘤微环境通常缺乏营养和氧气，但恶病质反应与肿瘤微环境的关系，以及重要的是与营养压力的关系尚不清楚。在这里，我们研究了代谢应激与 FN14 表达之间的联系。我们发现，在癌细胞系中，缺乏谷氨酰胺时 FN14 的表达被转录诱导。我们还表明，下游的谷氨酰胺分解代谢产物α-酮戊二酸（aKG）足以挽救谷氨酰胺剥夺促进的 FN14 诱导。由于 aKG 是组蛋白去甲基化酶的辅助因子，我们研究了组蛋白甲基化，发现缺乏谷氨酰胺时 FN14 启动子上的组蛋白 H3K4me3 增加，并通过 DM-aKG 补充得到挽救。最后，在小鼠癌症恶病质模型中，DM-aKG 可抑制体内 FN14 的表达和恶病质诱导的体重减轻。这些发现强调了代谢应激与癌症恶病质发展之间的联系。
