OLR1 promotes cell proliferation and invasion while represses apoptosis via regulating histone H3 lysine 18 lactylation-mediated LEMD1 in papillary thyroid cancer
Oxidized low density lipoprotein receptor 1 (OLR1) regulates glycolytic metabolism, lactate production and carcinogenesis, but its role in papillary thyroid cancer (PTC) is still unclear. The present study aimed to investigate the effect of OLR1 modification on PTC cellular functions and its interaction with histone H3 lysine 18 lactylation (H3K18la) and downstream molecular mechanisms. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1; OLR1 coding protein) and H3K18la expression was detected in twenty pairs of PTC and non-tumor tissues by immunohistochemistry. Overexpressed OLR1 and small interfering (si)RNA were transfected into two PTC cell lines (TPC-1 and IHH-4 cells). After which, oxamate (to reduce lactate production) or LEM domain containing 1 (LEMD1) siRNA combined with OLR1 overexpression plasmid was used to treat PTC cell lines. Furthermore, PTC xenograft mice were constructed for in vivo verification. LOX-1 and H3K18la expression was upregulated in PTC tissues versus non-tumor tissues and LOX-1 expression positively associated with H3K18la expression in PTC tissues. OLR1 overexpression facilitated cell proliferation and invasion but repressed cell apoptosis in PTC cell lines, while OLR1 siRNA revealed an opposite effect. OLR1 positively regulated lactate production, H3K18la expression and LEMD1 expression. Furthermore, a chromatin immunoprecipitation assay confirmed a direct binding between H3K18la and the LEMD1 promoter. H3K18la expression was lowered by oxamate-induced lactate reduction, which also attenuated the effect of OLR1 overexpression on PTC cell proliferation, apoptosis and invasion and downregulated LEMD1 expression. Moreover, LEMD1 siRNA weakened the effect of OLR1 overexpression on PTC cell proliferation, apoptosis and invasion. In vivo experiments revealed that OLR1 overexpression elevated tumor volume and weight and upregulated the expressions of LEMD1 and H3K18la; while LEMD1 knockdown reduced tumor volume and weight. In conclusion, OLR1 promotes PTC proliferation and invasion, while represses apoptosis through regulating H3K18la-mediated LEMD1.