CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer.
Long non-coding RNA (lncRNA), highly up-regulated in liver cancer (HULC) plays an important role in tumorigenesis. Depletion of HULC resulted in a significant deregulation of several genes involved in liver cancer. Although up-regulation of HULC expression in hepatocellular carcinoma has been reported, the molecular mechanisms remain unknown. In this study, we used in vivo and in vitro approaches to characterize cancer-dependent alterations in the chromatin organization and find a CREB binding site (encompassing from -67 to -53 nt) in the core promoter. Besides, we also provided evidence that PKA pathway may involved in up-regulation of HULC. Furthermore, we demonstrated HULC may act as an endogenous 'sponge', which down-regulates a series of microRNAs (miRNAs) activities, including miR-372. Inhibition of miR-372 leads to reducing translational repression of its target gene, PRKACB, which in turn induces phosphorylation of CREB. Over-expression of miR-372 decreases the association of CREB with the proximal promoter, followed by the dissociation of P300, resulting in a change of the histone 'code', such as in deacetylation and methylation. The study elucidates that fine tuning of HULC expression is part of an auto-regulatory loop in which it's inhibitory to expression and activity of miR-372 allows lncRNA up-regulated expression in liver cancer.
Wang
Jiayi
J
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People Republic of China.
Liu
Xiangfan
X
Wu
Huacheng
H
Ni
Peihua
P
Gu
Zhidong
Z
Qiao
Yongxia
Y
Chen
Ning
N
Sun
Fenyong
F
Fan
Qishi
Q
D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D002843:Chromatin; D017362:Cyclic AMP Response Element-Binding Protein; D006657:Histones; D035683:MicroRNAs; D022661:RNA, Untranslated; D014157:Transcription Factors; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D017868:Cyclic AMP-Dependent Protein Kinases; C517760:PRKACB protein, human