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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies with extremely poor prognosis. Therefore, revealing the critical molecules involved in HCC progression and prognosis is urgently needed. In this study, through combining public dataset and our cohort, we found a novel prognosis-related long non-coding RNA KB-68A7.1 in HCC. KB-68A7.1 was lowly expressed in HCC, whose low expression was associated with large tumour size, aggressive clinical characteristic, and poor survival. Gain- and loss-of-function assays demonstrated that KB-68A7.1 restricted HCC cellular proliferation, induced HCC cellular apoptosis, and suppressed HCC cellular migration and invasion  in vitro . Xenograft assays demonstrated that KB-68A7.1 suppressed HCC tumour growth and metastasis  in vivo . These functional assays suggested KB-68A7.1 as a tumour suppressor in HCC. Histone methyltransferase nuclear receptor binding SET domain-containing protein 1 (NSD1) was found to bind to KB-68A7.1. KB-68A7.1 was mainly distributed in the cytoplasm. The binding of KB-68A7.1 to NSD1 sequestrated NSD1 in the cytoplasm, leading to the reduction in nuclear NSD1 level. Through decreasing nuclear NSD1 level, KB-68A7.1 reduced di-methylation of histone H3 at lysine 36 (H3K36me2) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the promoter of  WNT10B , a target of NSD1. Thus, KB-68A7.1 repressed  WNT10B  transcription. The expression of WNT10B was negatively correlated with that of KB-68A7.1 in HCC tissues. Through repressing WNT10B, KB-68A7.1 further repressed Wnt/β-catenin signalling. Functional rescue assays showed that overexpression of WNT10B reversed the tumour-suppressive roles of KB-68A7.1, whereas the oncogenic roles of KB-68A7.1 depletion were abolished by Wnt/β-catenin signalling inhibitor. Overall, this study identified KB-68A7.1 as a lowly expressed and prognosis-related lncRNA in HCC, which suppressed HCC progression through binding to NSD1 and repressing Wnt/β-catenin signalling.

KB-68A7.1 Inhibits Hepatocellular Carcinoma Development Through Binding to NSD1 and Suppressing Wnt/β-Catenin Signalling