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

Abstract

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.

Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

“…In addition to the transcription factors, the EMT-related gene expression changes are regulated by non-coding RNAs, such as long noncoding RNAs (lncRNAs) and microRNAs ( Figure 1). A newly identified lncRNA, termed the metabolism-induced tumor activator 1 (MITA1), is induced by metabolic stress and contributes to metastasis [67]. MITA1 induces the transcription factor, Slug, and, in this indirect way, it also promotes EMT [67].…”

The Emerging Role of Long Non-Coding RNAs in the Metastasis of Hepatocellular Carcinoma

“…LncRNA-NEF and lncRNA-AWPPH can impede EMT progression and cancer metastasis via inhibiting the Wnt/β-catenin and PI3K/AKT pathway [26,35]. Another novel lncRNA MITA1, which is induced by energy stress, may promote EMT in a central step of HCC metastasis [72]. Intravasation and extravasation require the movement of cancer cells to the blood vessel, where lnc-ATB can regulate multiple steps of HCC metastasis, including EMT, invasion, and intravasation [41].…”

M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

“…It has been widely recognized that many lncRNAs are dysregulated and play an important part in cancer progression [2]. In HCC, lncRNAs have been reported to affect various malignant phenotypes, such as cell proliferation, motility, and glucose metabolism reprogramming [3][4][5]. However, investigations of the involvement of lncRNAs in aberrant lipid metabolism in HCC are few.…”