LncRNA AY promotes hepatocellular carcinoma metastasis by stimulating <i>ITGAV</i> transcription

Abstract

<b>Rationale</b>: Tumor metastasis is the main cause for cancer-related death. However, the driving molecules of metastasis remain largely unknown. Here, we aim to identify long non-coding RNAs (lncRNAs) critical for human hepatocellular carcinoma (HCC) metastasis. <b>Methods</b>: Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in sulfatide-treated cells. Mass spectrometry, protein arrays, and RNA pull-down experiments were used to identify proteins that interacted with lncRNA. Epigenetic analysis was used to study lncRNA-mediated regulation mechanisms. <b>Results</b>: We identified lncRNA AY927503 (AY) as a metastasis-associated molecule that was highly expressed in human hepatocellular carcinoma (HCC) and correlated with metastatic events and poor prognosis in patients with HCC. AY promoted HCC cell migration, stemness, 5-fluorouracil resistance, and metastasis in mice. However, knockdown of integrin αV (ITGAV) abolished AY-stimulated migration, cell viability in HCC cells or tube formation. AY strongly promoted <i>ITGAV</i> transcription and αVβ3 expression by interacting with the <i>ITGAV</i> promoter specifically and stimulating its activity. AY was identified to interact with histone 1FX (H1FX), but deletion of the central domain of AY (AY∆371-522) abolished H1FX binding and <i>ITGAV</i> promoter stimulation. AY significantly enriched H3K4Me3 and acH3K9/14 but reduced H3K27Me3 and H1FX occupancy on the <i>ITGAV</i> promoter, which remodeled chromatin structures for RNA polymerase II recruitment. Knockdown of H1FX abrogated <i>ITGAV</i> transcription stimulated by AY. <b>Conclusions</b>: Our findings suggested that lncRNA AY promoted HCC metastasis via induction of chromatin modification for <i>ITGAV</i> transcription as a pioneer factor and was a potential molecular signature for metastasis or poor prognosis in patients with HCC.