YTHDF1调控GID8介导的谷氨酰胺代谢以促进结直肠癌进展的m6A依赖性机制

YTHDF1 regulates GID8-mediated glutamine metabolism to promote colorectal cancer progression in m6A-dependent manner

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CANCER LETTERS

影响因子:10.1

分区:医学1区 Top / 肿瘤学2区

发表日期:2024 Oct 01

作者: Yicun Han, Yunzhou Pu, Xiaodie Liu, Zhiyi Liu, Yongqi Chen, Lei Tang, Jing Zhou, Qing Song, Qing Ji

DOI: 10.1016/j.canlet.2024.217186

摘要

表观遗传调控失调是癌症发展的标志之一，而YTHDF1在结直肠癌（CRC）患者中作为一种关键的表观遗传调控因子，其DNA拷贝数变异最高。本文旨在探讨YTHDF1过表达对CRC进展的具体贡献及其后果。通过对人类癌症数据库和临床CRC样本的多重生物信息学分析，鉴定GID8/Twa1为YTHDF1的重要下游靶点。YTHDF1通过m6A依赖性调节GID8的翻译效率，高表达的GID8与肿瘤更具侵袭性和预后不良相关。机制上，GID8通过调控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与代谢，从而促进CRC的恶性进展。抑制GID8能够在体内外减缓CRC的增殖和转移。总之，我们发现了一个与肿瘤细胞谷氨酰胺摄取和代谢相关的未知靶点GID8，凸显其在CRC治疗中的潜力。

Abstract

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 analyses 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 an 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.