MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Cancer Res. 2022 Jul 5;82(13):2444-2457. doi: 10.1158/0008-5472.CAN-21-4124.
N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into the regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3, whereas SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration-approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC.
This study finds that METTL3 promotes cancer metastasis by activating EGR1/Snail signaling in an m6A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.
N6-甲基腺嘌呤（m6A）甲基化是真核 mRNA 中丰富的修饰。越来越多的证据表明，RNA m6A 甲基化在癌症生物学的各个方面都起着作用。在这项研究中，我们旨在探索肿瘤转移中 RNA m6A 修饰的生物学作用，并为食管鳞状细胞癌（ESCC）确定新的治疗策略。全基因组 CRISPR/Cas9 功能筛选与高度侵袭性和转移性 ESCC 亚系模型的整合，导致鉴定出 METTL3，即 N6-腺苷-甲基转移酶复合物的催化亚基，是癌症转移的促进剂。METTL3 在 ESCC 肿瘤和转移组织中表达上调。体外和体内实验表明，METTL3 增加了 EGR1 mRNA 中的 m6A，并以 YTHDF3 依赖的方式增强其稳定性，从而激活 EGR1/Snail 信号。对 METTL3 表达的调控研究发现，KAT2A 增加了 METTL3 启动子区域的 H3K27 乙酰化水平并激活了 METTL3 的转录，而 SIRT2 则产生相反的效果。在由 1443 种小分子组成的美国食品和药物管理局批准的化合物库中进行的分子对接和计算筛选，确定了针对 METTL3 的化合物，以抑制癌症转移。最初开发用于治疗人类免疫缺陷病毒（HIV）感染的 Elvitegravir 通过直接靶向 METTL3 并增强其 STUB1 介导的蛋白酶体降解来抑制转移。总之，RNA m6A 修饰在癌症转移中很重要，用 Elvitegravir 靶向 METTL3 具有治疗 ESCC 的潜力。
这项研究发现，METTL3 通过 m6A 依赖性方式激活 EGR1/Snail 信号促进癌症转移，揭示了针对食管鳞状细胞癌中 METTL3 阻断的脆弱性。
