title: A long noncoding RNA perturbs the circadian rhythm of hepatoma cells to facilitate hepatocarcinogenesis.
abstract: Clock circadian regulator (CLOCK)/brain and muscle arnt-like protein-1 (BMAL1) complex governs the regulation of circadian rhythm through triggering periodic alterations of gene expression. However, the underlying mechanism of circadian clock disruption in hepatocellular carcinoma (HCC) remains unclear. Here, we report that a long noncoding RNA (lncRNA), highly upregulated in liver cancer (HULC), contributes to the perturbations in circadian rhythm of hepatoma cells. Our observations showed that HULC was able to heighten the expression levels of CLOCK and its downstream circadian oscillators, such as period circadian clock 1 and cryptochrome circadian clock 1, in hepatoma cells. Strikingly, HULC altered the expression pattern and prolonged the periodic expression of CLOCK in hepatoma cells. Mechanistically, the complementary base pairing between HULC and the 5' untranslated region of CLOCK mRNA underlay the HULC-modulated expression of CLOCK, and the mutants in the complementary region failed to achieve the event. Moreover, immunohistochemistry staining and quantitative real-time polymerase chain reaction validated that the levels of CLOCK were elevated in HCC tissues, and the expression levels of HULC were positively associated with those of CLOCK in clinical HCC samples. In functional experiments, our data exhibited that CLOCK was implicated in the HULC-accelerated proliferation of hepatoma cells in vitro and in vivo. Taken together, our data show that an lncRNA, HULC, is responsible for the perturbations in circadian rhythm through upregulating circadian oscillator CLOCK in hepatoma cells, resulting in the promotion of hepatocarcinogenesis. Thus, our finding provides new insights into the mechanism by which lncRNA accelerates hepatocarcinogenesis through disturbing circadian rhythm of HCC.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Minying
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Baodi
authors.initials: B
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China. Electronic address: zhangxd@nankai.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D056926:CLOCK Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental; D008297:Male; D008969:Molecular Sequence Data; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D056926:CLOCK Proteins