Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.
Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.
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DOI：
10.3390/genes14091818
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发表时间：
2023-09-19
期刊：
影响因子：
3.5
通讯作者：
Kong, Mei
中科院分区：
文献类型：
--
作者：
Ruiz, Bryan I.;Lowman, Xazmin H.;Yang, Ying;Fan, Qi;Wang, Tianhong;Wu, Hongmei;Hanse, Eric A.;Kong, Mei
既往研究表明，在结肠肿瘤中抑制TNF家族成员FN14（基因：TNFRSF12A）可降低炎症细胞因子的表达，减轻癌症诱导的恶病质。然而，调控FN14表达的分子机制尚不清楚。肿瘤微环境通常缺乏营养和氧气，然而恶病质反应如何与肿瘤微环境以及重要的营养应激相关尚不清楚。在这里，我们研究了代谢应激和FN14表达之间的联系。我们发现TNFRSF12A在谷氨酰胺剥夺过程中被转录诱导表达。我们还发现下游谷氨酰胺水解代谢产物α -酮戊二酸（aKG）足以挽救谷氨酰胺剥夺促进的TNFRSF12A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Tnfrsf12a启动子上的组蛋白H3K4me3在谷氨酰胺缺乏的条件下增加，并通过补充DM-aKG来恢复。最后，在小鼠癌症恶病质模型中，DM-aKG可以在体内抑制Tnfrsf12a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。
Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A) 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 TNFRSF12A 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 TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a 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.
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影响因子：
37.3
作者：
Denkert C;Budczies J;Weichert W;Wohlgemuth G;Scholz M;Kind T;Niesporek S;Noske A;Buckendahl A;Dietel M;Fiehn O
通讯作者：
Fiehn O
影响因子：
64.5
作者：
Johnston, Amelia J.;Murphy, Kate T.;Hoogenraad, Nicholas J.
通讯作者：
Hoogenraad, Nicholas J.
影响因子：
11.2
作者：
Kamphorst JJ;Nofal M;Commisso C;Hackett SR;Lu W;Grabocka E;Vander Heiden MG;Miller G;Drebin JA;Bar-Sagi D;Thompson CB;Rabinowitz JD
通讯作者：
Rabinowitz JD
DOI：
10.1073/pnas.1804755115
发表时间：
2018-10-09
影响因子：
11.1
作者：
Greenfield, Razi;Tabib, Amalia;Cedar, Howard
通讯作者：
Cedar, Howard
影响因子：
16.6
作者：
Gabra, Mari B. Ishak;Yang, Ying;Kong, Mei
通讯作者：
Kong, Mei