表观遗传学失调是癌症发展的一个标志，而 YTHDF1 是结直肠癌 (CRC) 患者中所有 N6-甲基腺苷 (m6A) 调节因子中 DNA 拷贝数变异最高的重要表观遗传调节因子。在这里，我们的目的是研究 YTHDF1 过度表达对 CRC 进展及其后果的具体贡献。通过对人类癌症数据库和临床 CRC 样本的多重生物信息分析，我们确定 GID8/Twa1 是 YTHDF1 的重要下游靶点。 YTHDF1 以 m6A 依赖性方式操纵 GID8 翻译效率，GID8 的高表达与更具侵袭性的肿瘤进展和较差的总体生存率相关。从机制上讲，GID8通过调节兴奋性氨基酸转运蛋白1（SLC1A3）和谷氨酰胺酶（GLS）维持活跃的谷氨酰胺摄取和代谢，与谷氨酰胺代谢需求密切相关，从而促进CRC的恶性进展。 GID8 的抑制可在体外和体内减弱 CRC 增殖和转移。总之，我们确定了一个先前未知的与肿瘤细胞中谷氨酰胺摄取和代谢有关的靶标，强调了 GID8 在治疗 CRC 中的潜力。版权所有 © 2024。由 Elsevier B.V 出版。

Dysregulation of epigenetics is a hallmark of cancer development, and YTHDF1 stands out as a crucial epigenetic regulator with the highest DNA copy number variation among all N6-methyladenosine (m6A) regulators in colorectal cancer (CRC) patients. Here, we aimed to investigate the specific contribution of YTHDF1 overexpression to CRC progression and its consequences. Through multiple bioinformatic analysis of human cancer databases and clinical CRC samples, we identified GID8/Twa1 as a crucial downstream target of YTHDF1. YTHDF1 manipulates GID8 translation efficiency in a m6A-dependent manner, and high expression of GID8 is associated with more aggressive tumor progression and poor overall survival. Mechanistically, GID8 is intimately associated with glutamine metabolic demands by maintaining active glutamine uptake and metabolism through the regulation of excitatory amino acid transporter 1 (SLC1A3) and glutaminase (GLS), thereby facilitating the malignant progression of CRC. Inhibition of GID8 attenuated CRC proliferation and metastasis both in vitro and in vivo. In summary, we identified a previously unknown target pertaining to glutamine uptake and metabolism in tumor cells, underscoring the potential of GID8 in the treatment of CRC.Copyright © 2024. Published by Elsevier B.V.