title: LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2.
abstract: Long non-coding RNA HOTAIR predicts negative tumor prognosis and exhibits oncogenic activity. Herein, we demonstrate HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Mechanistically, HOTAIR reduces the recuritment of the CREB, P300, RNA polII onto the SETD2 promoter region that inhibits SETD2 expression and its phosphorylation. Thereby, the SETD2 binding capacity to substrate histone H3 is weakened, triggering a reduction of trimethylation on histone H3 thirty-sixth lysine, and thereby the H3K36me3-hMSH2-hMSH6-SKP2 complex is also decreased. Strikingly, the complex occupancy on chromosome is depressed, preventing from mismatch DNA repair. While reducing the degradation capacity of Skp2 for aging histone H3 bound to damaged DNA, the aging histone repair is impaired. Furthermore, that the damaged DNA escaped to repair can causes microsatellite instability(MSI) and abnormal expression of cell cycle related genes that may trigger the hepatocarcinogenesis. This study provides evidence for HOTAIR to promote tumorigenesis via downregulating SETD2 in liver cancer stem cells.
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: An
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Wu
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Qidi
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gui
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Tianming
authors.initials: T
authors.lastname: Li
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Pu
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Lu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000473:pathology*; D062085:RNA, Long Noncoding / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C561566:HOTAIR long untranslated RNA, human; D062085:RNA, Long Noncoding; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human
keywords: DNA mismatch repair; SETD2; liver cancer stem cell; lncRNA HOTAIR; microsatellite instability