Methylation of the promoter region of the Tight Junction Protein-1 by DNMT1 induces Epithelial-Mesenchymal Transition-like features in multiple myeloma

Abstract The molecular alterations that initiate the development of multiple myeloma (MM) are not fully understood. Our results revealed that TJP1 was downregulated in MM and positively related to the overall survival of MM patients in TCGA database and patient samples. In parallel, cell adhesion capacity representing MM metastasis was decreased in MM patients compared with healthy samples, together with the significantly activated epithelial-to-mesenchymal-transition (EMT) transcriptional like patterns of MM cells. Further analyses demonstrated that TJP1 negatively regulated EMT and consequently positively regulated cell adhesion in MM from TCGA database and MM1s cells. Furthermore, the methylation level of each CpG site on TJP1 promoter was negatively correlated with TJP1 expression levels. qRT-PCR and western blot assays demonstrated that methylase DNMT1 regulated the methylation of TJP1. Finally, the treatment of combination of MM clinical medicine Bortezomib, methylation inhibitor or TJP1-overexpression significantly suppressed the viability and progression of tumor cells of MM orthotopic models. In summary, our results indicate that DNMT1 promotes the methylation of TJP1 promoter, thereby decreases its expression and regulates the development of EMT-inhibited MM cell adhesion. Therefore, methylation of TJP1 is a potential therapeutic agent to prevent the progression of MM disease.