Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People Republic of China.
Nucleic Acids Res. 2010 Sep;38(16):5366-83. doi: 10.1093/nar/gkq285. Epub 2010 Apr 27.
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.
长链非编码 RNA（lncRNA）在肝癌中高度上调（HULC），在肿瘤发生中发挥重要作用。HULC 的耗竭导致涉及肝癌的几个基因的显著失调。尽管已经报道了 HULC 在肝细胞癌中的表达上调，但分子机制仍不清楚。在这项研究中，我们使用体内和体外方法来描述染色质组织中与癌症相关的改变，并在核心启动子中找到一个 CREB 结合位点（包含 -67 到 -53 个核苷酸）。此外，我们还提供了证据表明 PKA 途径可能参与了 HULC 的上调。此外，我们证明 HULC 可以作为一种内源性“海绵”，下调一系列 microRNAs（miRNAs）的活性，包括 miR-372。抑制 miR-372 会减少其靶基因 PRKACB 的翻译抑制，从而导致 CREB 的磷酸化。miR-372 的过表达会减少 CREB 与近端启动子的结合，随后 P300 解离，导致组蛋白“密码”发生变化，如去乙酰化和甲基化。该研究阐明了 HULC 表达的精细调控是其自身负反馈环的一部分，它抑制 miR-372 的表达和活性，从而允许 lncRNA 在肝癌中高表达。
