Metabolism-induced tumor activator 1 (MITA1), an Energy Stress-Inducible Long Noncoding RNA, Promotes Hepatocellular Carcinoma Metastasis

Metastasis is the main cause of cancer-related death, yet the underlying mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) are emerging as crucial regulators of malignancies; however, their functions in tumor metastasis remain largely unexplored. In this study, we identify a lncRNA, termed metabolism-induced tumor activator 1 (MITA1), which is up-regulated in hepatocellular carcinoma (HCC) and contributes to metastasis. MITA1, a chromatin-enriched lncRNA discovered by our nuclear RNA sequencing, is significantly induced by energy stress. This induction of MITA1 is governed by the liver kinase B1-adenosine monophosphate-activated protein kinase (LKB1-AMPK) pathway and DNA methylation. Knockdown of MITA1 dramatically inhibits the migration and invasion of liver cancer cells in vitro and HCC metastasis in vivo. Mechanistically, MITA1 promotes the epithelial-mesenchymal transition, an early and central step of metastasis, which may partly attribute to an increase in Slug (snail family zinc finger 2) transcription. MITA1 deficiency reduces the expression of the mesenchymal cell markers, especially Slug, whereas Slug overexpression greatly impairs the effects of MITA1 deficiency on HCC migration and invasion. Correspondingly, there is a positive correlation between the levels of MITA1 and Slug precursors in HCC tissues. Conclusion: Our data reveal MITA1 as a crucial driver of HCC metastasis, and highlight the identified AMPK-MITA1-Slug axis as a potential therapeutic strategy for HCC.