title: HOTAIR Epigenetically Modulates PTEN Expression via MicroRNA-29b: A Novel Mechanism in Regulation of Liver Fibrosis.
abstract: Homeobox transcript antisense RNA (HOTAIR), as a long intergenic non-coding RNA (lincRNA), is upregulated in various cancers and involved in diverse cellular functions. However, its role in liver fibrosis is unclear. In this study, HOTAIR expression was upregulated in hepatic stellate cells (HSCs) in vivo and in vitro during liver fibrosis. HOTAIR knockdown suppressed HSC activation including α-smooth muscle actin (α-SMA) and typeIcollagen in vitro and in vivo. Both HSC proliferation and cell cycle were inhibited by HOTAIR knockdown. Notably, inhibition of HOTAIR led to an increase in PTEN, associated with the loss of DNA methylation. miR-29b-mediated control of PTEN methylation was involved in the effects of HOTAIR knockdown. HOTAIR was confirmed a target of miR-29b and lack of the miR-29b binding site in HOTAIR prevented the suppression of miR-29b, suggesting HOTAIR contributes to PTEN expression downregulation via sponging miR-29b. Interestingly, increased HOTAIR was also observed in hepatocytes during liver fibrosis. Loss of HOTAIR additionally led to the increase in PTEN and the reduction in typeIcollagen in hepatocytes. Collectively, we demonstrate that HOTAIR downregulates miR-29b expression and attenuates its control on epigenetic regulation, leading to enhanced PTEN methylation, which contributes to the progression of liver fibrosis.
authors.affiliation: Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Gastroenterology, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 201600, China; Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Yu
authors.affiliation: Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Bicheng
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: dongpeihong111@163.com.
authors.forename: Peihong
authors.initials: P
authors.lastname: Dong
authors.affiliation: Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: 120378196@qq.com.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Zheng
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D018450:Disease Progression; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D020413:3' Untranslated Regions; D004248:DNA (Cytosine-5-)-Methyltransferases; D048049:Extracellular Signal-Regulated MAP Kinases; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D062085:RNA, Long Noncoding; D000097584:DNA Methyltransferase 3B; C561566:HOTAIR long untranslated RNA, human; C532045:MIRN29a microRNA, human
keywords: DNA methylation; DNA methyltransferase; DNMT; HOTAIR; PTEN; homeobox transcript antisense RNA; microRNA-29b; phosphatase and tensin homolog deleted on chromosome 10