Genome-wide target interactome profiling reveals a novel EEF1A1 epigenetic pathway for oncogenic lncRNA MALAT1 in breast cancer

摘要

Breast cancer is the most common cancer in women worldwide, accounting for approximately 500,000 deaths each year. MALAT1 is a highly conserved long noncoding RNA (lncRNA), and its increased expression is associated with relapse and metastatic progression in breast cancer. We performed RNA reverse transcription-associated trap sequencing (RAT-seq) to characterize the genome-wide target interaction network for MALAT1 and showed that MALAT1 interacted with multiple pathway target genes that are closely related to tumor progression and metastasis. Notably, MALAT1 bound to the promoter regulatory element of the translation elongation factor 1-alpha 1 gene EEF1A1. Knockdown of MALAT1 by shRNA caused significant downregulation of EEF1A1 in breast cancer MDA-MB231 and SKRB3 cells. Using a luciferase reporter assay, we showed that knockdown of MALAT1 reduced the promoter activity of EEF1A1 in these two breast cancer cells. Chromatin immunoprecipitation (ChIP) assay indicated that MALAT1 regulated EEF1A1 by altering the histone 3 lysine 4 (H3K4) epigenotype in the gene promoter. MALAT1 was overexpressed in breast cancer tissues and breast cancer cells. Knockdown of MALAT1 reduced cell proliferation and invasion by arresting cells at the G0/G1 phase. Ectopic overexpression of EEF1A1 reversed the altered tumor phenotypes induced by MALAT1 shRNA treatment. These data suggest an epigenetic mechanism by which MALAT1 lncRNA facilitates a pro-metastatic phenotype in breast cancer by trans-regulating EEF1A1.