The HNF1α-regulated lncRNA HNF1A-AS1 reverses the malignancy of hepatocellular carcinoma by enhancing the phosphatase activity of SHP-1

Abstract

BackgroundOur previous study has demonstrated that hepatocyte nuclear factor 1α (HNF1α) exerts potent therapeutic effects on hepatocellular carcinoma (HCC). However, the molecular mechanisms by which HNF1α reverses HCC malignancy need to be further elucidated.MethodslncRNA microarray was performed to identify the long noncoding RNAs (lncRNAs) regulated by HNF1α. Chromatin immunoprecipitation and luciferase reporter assays were applied to clarify the mechanism of the transcriptional regulation of HNF1α to HNF1A antisense RNA 1 (HNF1A-AS1). The effect of HNF1A-AS1 on HCC malignancy was evaluated in vitro and in vivo. RNA pulldown, RNA-binding protein immunoprecipitation and the Bio-Layer Interferometry assay were used to validate the interaction of HNF1A-AS1 and Src homology region 2 domain-containing phosphatase 1 (SHP-1).ResultsHNF1α regulated the expression of a subset of lncRNAs in HCC cells. Among these lncRNAs, the expression levels of HNF1A-AS1 were notably correlated with HNF1α levels in HCC cells and human HCC tissues. HNF1α activated the transcription of HNF1A-AS1 by directly binding to its promoter region. HNF1A-AS1 inhibited the growth and the metastasis of HCC cells in vitro and in vivo. Moreover, knockdown of HNF1A-AS1 reversed the suppressive effects of HNF1α on the migration and invasion of HCC cells. Importantly, HNF1A-AS1 directly bound to the C-terminal of SHP-1 with a high binding affinity (KD = 59.57 ± 14.29 nM) and increased the phosphatase activity of SHP-1. Inhibition of SHP-1 enzymatic activity substantially reversed the HNF1α- or HNF1A-AS1-induced reduction on the metastatic property of HCC cells.ConclusionsOur data revealed that HNF1A-AS1 is a direct transactivation target of HNF1α in HCC cells and involved in the anti-HCC effect of HNF1α. HNF1A-AS1 functions as phosphatase activator through the direct interaction with SHP-1. These findings suggest that regulation of the HNF1α/HNF1A-AS1/SHP-1 axis may have beneficial effects in the treatment of HCC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0813-1) contains supplementary material, which is available to authorized users.

Cytotoxic potentials of S. cumini methanolic seed kernel extract in human hepatoma HepG2 cells

“…It has been shown that the expression of HFN‐1α is associated with cancer risk in several tumors, including hepatocellular and pancreatic carcinoma, renal cancer, ovarian cancer, endometrial cancer, and prostate cancer . However, recent studies also reported the antitumor potentials of HFN‐1α . At this juncture, it is not clear whether the downregulation of HFN‐1α observed in this study is responsible for apoptosis induction and hence, further studies are warranted on these lines.…”

“…29,30 However, recent studies also reported the antitumor potentials of HFN-1α. 31,32 At this juncture, it is not clear whether the downregulation of HFN-1α observed in this study is responsible for apoptosis induction and hence, further studies are warranted on these lines.…”

The HNF1α-Regulated LncRNA HNF1α-AS1 Is Involved in the Regulation of Cytochrome P450 Expression in Human Liver Tissues and Huh7 Cells

“…Mechanistically, HNF1a-AS1 may function as a competing endogenous RNA to repress miRNA-mediated post-transcriptional regulation in cancer progression (Fang et al, 2017). Transcriptional regulation of HNF1a-AS1 by HNF1a has also been reported in hepatocellular carcinoma (Ding et al, 2018). HNF1a-AS1 was further shown to directly bind to the C terminus of Scr homology region 2 domain-containing phosphatase 1 and increase the phosphatase activity of this protein, which can reverse the malignancy of hepatocellular carcinoma (Ding et al, 2018).…”

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

“…A recent study revealed that lncRNA TSLNC8 (also known as LINC00589) exerts its tumor suppressive activity through the inactivation of the IL-6/STAT3 signaling pathway via physically interacting with TKT and STAT3, and thus inhibiting STAT3 phosphorylation and transcriptional activity in HCC [36]. Another study indicated that lncRNA HNF1A-AS1 (HNF1A antisense RNA 1) can inhibit the growth and metastasis of HCC by activating phosphatase through direct binding with the C-terminal of SHP-1 (SH2-containing protein tyrosine phosphatase-1) [30]. However, the effect of lncRNAs on gene expression through protein modification is not limited to the phosphorylation of target proteins.…”