title: Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway.
abstract: HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARA mRNA by eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo. Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the retinoid receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Zelin
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Minying
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China. Key Laboratory of Cancer Prevention and Therapy, Tianjin Department of Hepatobiliary Tumor, Tianjin, China.
authors.forename: Tianqiang
authors.initials: T
authors.lastname: Song
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Baodi
authors.initials: B
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China. zhangxd@nankai.edu.cn yelihong@nankai.edu.cn.
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China. zhangxd@nankai.edu.cn yelihong@nankai.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003066:Coenzyme A Ligases / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C574685:HULC long non-coding RNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D047493:PPAR alpha; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D003066:Coenzyme A Ligases; C583414:ACSL1 protein, human