LncRNA RUNX1-IT1 which is downregulated by hypoxia-driven histone deacetylase 3 represses proliferation and cancer stem-like properties in hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma (HCC) is characterised by a hypoxic microenvironment and a high rate of heterogeneity and recurrence, and the presence of cancer stem cells (CSCs) in HCC may well explain both of these pathological properties. There is mounting evidence that long non-coding RNAs (lncRNAs) participate in carcinogenesis and maintain cancer stemness of HCC cells. However, the expression modes, regulatory mechanisms and potential roles of stemness-related lncRNAs in HCC are still obscure. LncRNA RUNX1-IT1 is the intronic transcript 1 of the RUNX1, which is also known as chromosome 21 open-reading frame 96 (C21orF96). Although the functions of the RUNX1 have been identified in different diseases, the function and its potential mechanisms of the lncRNA RUNX1-IT1 in HCC still remains to be largely unknown. In this study, we verified that the expression of LncRNA RUNX1-IT1 was decreased in GEO data set, HCC samples and correlated with unfavourable clinicopathologic characteristics and poor prognosis. RUNX1-IT1 repressed HCC cell proliferation, cell cycle progression, invasion and cancer stemness and induced apoptosis in vitro. Overexpression of RUNX1-IT1 impaired the growth, metastasis and stem-like features of HCC cells in vivo. Mechanistically, RUNX1-IT1 directly bound to miR-632 and acted as competing endogenous RNA to facilitate the expression of the miR-632 target gene GSK-3β and subsequently modulate the WNT/β-catenin pathway in HCC cells. Furthermore, hypoxia-driven histone deacetylase 3 (HDAC3), as an upstream regulatory mechanism, was critical for the downregulation of RUNX1-IT1 in HCC. Thus, lncRNA RUNX1-IT1, as a regulator of hypoxia, may function as a potential therapeutic target for conquering HCC.

Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma

“…Hypoxia, which resulted from rapid tumor growth and vascular abnormality, has been identified as a critical driver of HCC progression (Jing et al, 2019). Our previous studies have demonstrated that hypoxia contributes to the growth and metastasis of HCC via regulating protein-coding genes and non-coding RNAs, such TUFT1 (Dou et al, 2019b), VASP (Liu et al, 2018), miR-1296 (Xu et al, 2017a), and RUNX1-IT1 (Sun et al, 2020). Hypoxia has been recognized as an inducer of the activation of the TLR4/MyD88/NF-κB pathway in hepatic ischemia/reperfusion injury and liver fibrosis (Kang et al, 2017;Du et al, 2019).…”

Long noncoding RNA PICSAR/miR‐588/EIF6 axis regulates tumorigenesis of hepatocellular carcinoma by activating PI3K/AKT/mTOR signaling pathway

“…Long noncoding RNAs (lncRNAs) are a class of transcribed RNA molecules with a length more than 200 nucleotides with limited or no protein‐coding capacity 5 . Accumulating studies have reported that lncRNAs play critical roles in cancer progression and development and participate in diverse biological functions such as cell proliferation, apoptosis, stem cell differentiation, and metastasis 6,7 . The molecular mechanisms by which lncRNAs exert their biological function are diverse and complex.…”

Geniposide inhibits proliferation and induces apoptosis of diffuse large B-cell lymphoma cells by inactivating the HCP5/miR-27b-3p/MET axis

“…Accumulating evidence supports the hypothesis that lncRNAs participate in regulating gene transcription, mRNA stabilization, and protein synthesis and degradation [15]. Furthermore, lncRNAs have been crucial regulators in the occurrence and progression of various human cancers, including DLBCL [16][17][18][19][20][21]. The HLA complex P5 (HCP5) is a cancer-related lncRNA and has been investigated in breast cancer [22], follicular thyroid carcinoma (FTC) [23], lung adenocarcinoma (LUAD) [24], glioma [25], and GC [26].…”