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.