Genome-wide target interactome profiling reveals a novel <i>EEF1A1</i> epigenetic pathway for oncogenic lncRNA <i>MALAT1</i> in breast cancer.

Abstract

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