Methylation-dependent MCM6 repression induced by LINC00472 inhibits triple-negative breast cancer metastasis by disturbing the MEK/ERK signaling pathway

摘要

Long noncoding RNAs (lncRNAs) have been identified to be dysregulated in multiple cancer types, which are speculated to be of vital significance in regulating several hallmarks of cancer biology. Triple-negative breast cancer (TNBC) is acknowledged as an aggressive subtype of breast cancer. In this study, we found the lncRNA LINC00472 was poorly expressed in TNBC tissues and cells. Overexpression of LINC00472 could inhibit the proliferation, invasion and migration of MDA-MB-231 cells. On the contrary, minichromosome maintenance complex component 6 (MCM6) was highly expressed in TNBC tissues and MDA-MB-231 cells due to suppressed methylation. LINC00472 induced site-specific DNA methylation and reduced the MCM6 expression by recruiting DNA methyltransferases into the MCM6 promoter. Since the restoration of MCM6 weakened the tumor-suppressive effect of LINC00472 on MDA-MB-231 cells, LINC00472 potentially acted as a tumor suppressor by inhibiting MCM6. In addition, in vivo experiments further substantiated that overexpression of LINC00472 inhibited tumor growth and metastasis to lungs by decreasing the expression of MCM6. Overall, the present study demonstrated that LINC00472-mediated epigenetic silencing of MCM6 contributes to the prevention of tumorigenesis and metastasis in TNBC, providing an exquisite therapeutic target for TNBC.