title: HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc.
abstract: c-Myc is regarded as a transcription factor, but the basis for its function remains unclear. Here, we define a long noncoding RNA (lncRNA)/protein complex that mediates the transcriptional activation by c-Myc in breast cancer cells. Among 388 c-Myc target genes in human MCF-7 breast cancer cells, we found that their promoters could be occupied by the oncoprotein HBXIP. We confirmed that the HBXIP expression correlated with expression of the c-Myc target genes cyclin A, eIF4E, and LDHA. RNAi-mediated silencing of HBXIP abolished c-Myc-mediated upregulation of these target genes. Mechanistically, HBXIP interacted directly with c-Myc through the leucine zippers and recruited the lncRNA Hotair along with the histone demethylase LSD1, for which Hotair serves as a scaffold. Silencing of HBXIP, Hotair, or LSD1 was sufficient to block c-Myc-enhanced cancer cell growth in vitro and in vivo. Taken together, our results support a model in which the HBXIP/Hotair/LSD1 complex serves as a critical effector of c-Myc in activating transcription of its target genes, illuminating long-standing questions on how c-Myc drives carcinogenesis.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Runping
authors.initials: R
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, P.R. China. yelihong@nankai.edu.cn zhangxd@nankai.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China. yelihong@nankai.edu.cn zhangxd@nankai.edu.cn.
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D016259:Genes, myc; D064593:Heterografts; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C561566:HOTAIR long untranslated RNA, human; C110719:LAMTOR5 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D056466:Histone Demethylases; C495195:KDM1A protein, human