SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle.
SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle.
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DOI：
10.1002/advs.202301871
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发表时间：
2023-10
期刊：
影响因子：
15.1
通讯作者：
Sun, Li
中科院分区：
文献类型：
--
作者：
She, Xiaowei;Wu, Qi;Rao, Zejun;Song, Da;Huang, Changsheng;Feng, Shengjie;Liu, Anyi;Liu, Lang;Wan, Kairui;Li, Xun;Yu, Chengxin;Qiu, Cheng;Luo, Xuelai;Hu, Junbo;Wang, Guihua;Xu, Feng;Sun, Li
MCT1是在单羧酸转运体中发现的关键蛋白，在调节乳酸穿梭中起重要作用。然而，调控MCT1的转录后修饰尚不清楚。在这项研究中，据报道SETDB1与MCT1相互作用，导致其稳定。这些发现揭示了MCT1的一种新的翻译后修饰，其中SETDB1甲基化发生在体外和体内的K473位点。这种甲基化抑制了MCT1和Tollip之间的相互作用，从而阻断了Tollip介导的MCT1自噬降解。此外，MCT1 K473三甲基化促进结直肠癌（CRC）中肿瘤糖酵解和肿瘤相关巨噬细胞的M2样极化，从而增强乳酸穿梭。在临床研究中，MCT1 K473三甲基化被发现上调，并与CRC的肿瘤进展和总生存呈正相关。这一发现表明SETDB1介导的K473位点三甲基化是乳酸穿梭和肿瘤进展的重要调节机制。此外，MCT1 K473甲基化可能是CRC的潜在预后生物标志物和有希望的治疗靶点。这一发现表明SETDB1介导的K473位点三甲基化是乳酸穿梭和肿瘤进展的重要调节机制。此外，MCT1 K473甲基化可能是结直肠癌的潜在预后生物标志物和有希望的治疗靶点。
MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post‐transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post‐translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip‐mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri‐methylation promotes tumor glycolysis and M2‐like polarization of tumor‐associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri‐methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1‐mediated tri‐methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC. This discovery suggests that SETDB1‐mediated tri‐methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for colorectal cancer.
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