ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

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 studied using 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.

hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease

“…In these instances, both A1 and A2/B1 specifically recognize a G-quadruplex structure, like that in telomeric DNA, in many of the promoter regions they regulate [68][69][70][71]. A1 and A2/B1 are found to be overexpressed in a number of cancers [63,[72][73][74][75]. This is characterized to result in an aberrant up-regulation of transcriptional targets like TRA2B (encoding Transformer 2β) in colon cancer [68] or KRAS (encoding Kirsten rat sarcoma viral oncogene homolog) in pancreatic cancer [69,71].…”