Department of General Practice, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510150, P.R. China.
Department of Anesthesiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510150, P.R. China.
J Exp Clin Cancer Res. 2021 Feb 11;40(1):64. doi: 10.1186/s13046-021-01858-1.
Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown.
Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studiedusing cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD.
We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation.
Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.
新出现的证据表明，代谢重编程和异常乙酰化修饰在肺腺癌（LUAD）进展中起着重要作用，尽管其机制在很大程度上尚不清楚。
在这里，我们使用了三个公共数据库（Oncomine、基因表达综合数据库[GEO]、癌症基因组图谱[TCGA]）来分析 LUAD 中 ESCO2（凝聚 1 同源物 2 建立）的表达。使用体外细胞增殖、集落形成、细胞迁移和侵袭测定以及体内小鼠异种移植模型研究 ESCO2 的生物学功能。使用基因集富集分析（GSEA）和质谱搜索 ESCO2 相互作用蛋白。使用 RT-PCR 联合限制性消化进行丙酮酸激酶 M1/2（PKM）mRNA 剪接测定。使用葡萄糖摄取测定和乳酸生成研究 LUAD 细胞代谢。ESCO2 表达在 LUAD 组织中显著上调，并且 ESCO2 表达较高的 LUAD 患者预后较差。
我们发现 ESCO2 促进了 LUAD 细胞在体外和体内的增殖和转移代谢重编程。在机制上，ESCO2 通过抑制 hnRNPA1 核转位，增加 hnRNPA1 与 PKM mRNA 外显子 9（EI9）侧翼内含子序列的结合，最终抑制 PKM1 同工型形成并诱导 PKM2 同工型形成。
我们的研究结果证实 ESCO2 是促进 LUAD 恶性进展的关键因素，并表明它是治疗 LUAD 的新靶点。
