Hui-Er Zhu1, Tao Li2, Shengnan Shi3, De-Xiong Chen1, Weiping Chen4, Hui Chen5. 1. Department of General Practice, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510150, P.R. China. 2. Department of Anesthesiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510150, P.R. China. 3. State Key Laboratory of Animal Breeding, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, South China Key Laboratory of Animal Nutrition and Feed, Ministry of Agriculture, Guangzhou, 510640, P. R. China. 4. Department of Respiratory, The People's Hospital of Qingyuan, Sixth Affiliate Hospital of Guangzhou Medical University, Qingyuan, 511518, P. R. China. 1806973726@qq.com. 5. Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510150, P.R. China. chenhui7320@126.com.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Zorawar S Noor; Amy L Cummings; McKenna M Johnson; Marshall L Spiegel; Jonathan W Goldman Journal: Semin Respir Crit Care Med Date: 2020-05-25 Impact factor: 3.119
Authors: Alice T Shaw; Benjamin J Solomon; Benjamin Besse; Todd M Bauer; Chia-Chi Lin; Ross A Soo; Gregory J Riely; Sai-Hong Ignatius Ou; Jill S Clancy; Sherry Li; Antonello Abbattista; Holger Thurm; Miyako Satouchi; D Ross Camidge; Steven Kao; Rita Chiari; Shirish M Gadgeel; Enriqueta Felip; Jean-François Martini Journal: J Clin Oncol Date: 2019-03-20 Impact factor: 44.544