Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interacting with EZH2

Abstract

<jats:title>Abstract</jats:title> <jats:p>Background Dysregulations of lncRNA are responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. Growing number of lncRNAs have been reported in HCC but their functional and mechanistic roles remain unclear. Methods Gene Set Enrichment Analysis was used to investigate the molecular mechanism of lncRNA UPK1A antisense RNA 1 (UPK1A-AS1). CCK-8 assay, EdU assay, flow cytometry, western blot, and xenograft assay were used to confirm the role of UPK1A-AS1 in proliferation of HCC cells both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. Bioinformatics analysis and qRT-PCR were performed to explore the interplay between UPK1A-AS1 and Enhancer of Zeste Homologue 2 (EZH2). RNA immunoprecipitation, RNA-pull down assay, western blot, qRT-PCR, and were conducted to confirm the interaction between UPK1A-AS1 and EZH2. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA-seq data from TCGA datasets. Results We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle related genes including CyclinD1, CDK2, CDK4, CCNB1 and CCNB2 were significantly upregulated in HCC cells with UPK1A-AS1 overexpression. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to the increasing trimethylation of H27K3. Targeting EZH2 with specific siRNA impaired UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression related genes. Moreover, UPK1A-AS1 was significantly upregulated in HCC, and upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions Our study reveals that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression in an EZH2-dependent manner, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.</jats:p>

Dysregulation of EZH2/miR-138-5p Axis Contributes to Radiosensitivity in Hepatocellular Carcinoma Cell by Downregulating Hypoxia-Inducible Factor 1 Alpha (HIF-1α)

“…Silencing EZH2 has been found to effectively inhibit malignant behaviors of tumor cells, which has hence spurred tremendous efforts to find novel and efficient EZH2 inhibitors [13,14]. One of such inhibitors is miR-138-5p, which is a noncoding RNA that can suppress the progressive behavior of HCC cells [15,16].…”