Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation

Overview

Journal Hepatology

Specialty Gastroenterology

Date 2019 Mar 14

PMID 30865310

Citations 69

Authors

Yun-Long Wang

Jin-Yu Liu

Jin-E Yang

Xiao-Man Yu

Zhan-Li Chen

Ya-Jing Chen

Ming Kuang

Ying Zhu

Shi-Mei Zhuang

Affiliations

Soon will be listed here.

Abstract

Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a limited number of them have been functionally characterized. Here, we identified an oncogenic lncRNA, named lnc-UCID (lncRNA up-regulating CDK6 by interacting with DHX9). Lnc-UCID was up-regulated in hepatocellular carcinoma (HCC), and a higher lnc-UCID level was correlated with shorter recurrence-free survival of HCC patients. Both gain-of-function and loss-of function studies revealed that lnc-UCID enhanced cyclin-dependent kinase 6 (CDK6) expression and thereby promoted G1/S transition and cell proliferation. Studies from mouse xenograft models revealed that tumors derived from lnc-UCID-silenced HCC cells had a much smaller size than those from control cells, and intratumoral injection of lnc-UCID small interfering RNA suppressed xenograft growth. Mechanistically, the 850-1030-nt domain of lnc-UCID interacted physically with DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), an RNA helicase. On the other hand, DHX9 post-transcriptionally suppressed CDK6 expression by binding to the 3'-untranslated region (3'UTR) of CDK6 mRNA. Further investigation disclosed that lnc-UCID enhanced CDK6 expression by competitively binding to DHX9 and sequestering DHX9 from CDK6-3'UTR. In an attempt to explore the mechanisms responsible for lnc-UCID up-regulation in HCC, we found that the lnc-UCID gene was frequently amplified in HCC. Furthermore, miR-148a, whose down-regulation was associated with an increase of lnc-UCID in HCC, could bind lnc-UCID and inhibit its expression. Conclusion: Up-regulation of lnc-UCID, which may result from amplification of its gene locus and down-regulation of miR-148a, can promote HCC growth by preventing the interaction of DHX9 with CDK6 and subsequently enhancing CDK6 expression. These findings provide insights into the biological functions of lncRNAs, the regulatory network of cell cycle control, and the mechanisms of HCC development, which may be exploited for anticancer therapy.

Citing Articles

HBV-associated hepatocellular carcinomas inhibit antitumor CD8 T cell via the long noncoding RNA HDAC2-AS2.

Gao Y, Zhang Z, Huang X, You M, Du C, Li N Nat Commun. 2025; 16(1):2055.

PMID: 40021665 PMC: 11871238. DOI: 10.1038/s41467-025-57367-8.

LINC01094 promotes gastric cancer through dual targeting of CDKN1A by directly binding RBMS2 and HDAC1.

Zhou X, Gu C, Xiao L, Hu L, Chen G, Zuo F Biol Direct. 2024; 19(1):137.

PMID: 39719596 PMC: 11669238. DOI: 10.1186/s13062-024-00582-y.

Deciphering the nexus between long non-coding RNAs and endoplasmic reticulum stress in hepatocellular carcinoma: biomarker discovery and therapeutic horizons.

Goyal H, Parwani S, Kaur J Cell Death Discov. 2024; 10(1):451.

PMID: 39448589 PMC: 11502918. DOI: 10.1038/s41420-024-02200-2.

Prognostic Value of an Immune Long Non-Coding RNA Signature in Liver Hepatocellular Carcinoma.

Kong R, Wang N, Zhou C, Lu J J Microbiol Biotechnol. 2024; 34(4):958-968.

PMID: 38494878 PMC: 11091670. DOI: 10.4014/jmb.2308.08022.

What are the changes in the hotspots and frontiers of microRNAs in hepatocellular carcinoma over the past decade?.

Zhang L, Chen Z, Wei X, Li J, Chen G World J Clin Oncol. 2024; 15(1):145-158.

PMID: 38292666 PMC: 10823937. DOI: 10.5306/wjco.v15.i1.145.

References

Myohanen S, Baylin S . Sequence-specific DNA binding activity of RNA helicase A to the p16INK4a promoter. J Biol Chem. 2000; 276(2):1634-42. DOI: 10.1074/jbc.M004481200. View

Cram E, Liu B, Bjeldanes L, Firestone G . Indole-3-carbinol inhibits CDK6 expression in human MCF-7 breast cancer cells by disrupting Sp1 transcription factor interactions with a composite element in the CDK6 gene promoter. J Biol Chem. 2001; 276(25):22332-40. DOI: 10.1074/jbc.M010539200. View

Bracken A, Ciro M, Cocito A, Helin K . E2F target genes: unraveling the biology. Trends Biochem Sci. 2004; 29(8):409-17. DOI: 10.1016/j.tibs.2004.06.006. View

Man X, Tang L, Zhang B, Li S, Qiu X, Wu M . Upregulation of Glypican-3 expression in hepatocellular carcinoma but downregulation in cholangiocarcinoma indicates its differential diagnosis value in primary liver cancers. Liver Int. 2005; 25(5):962-6. DOI: 10.1111/j.1478-3231.2005.01100.x. View

Hartman T, Qian S, Bolinger C, Fernandez S, Schoenberg D, Boris-Lawrie K . RNA helicase A is necessary for translation of selected messenger RNAs. Nat Struct Mol Biol. 2006; 13(6):509-16. DOI: 10.1038/nsmb1092. View

Robb G, Rana T . RNA helicase A interacts with RISC in human cells and functions in RISC loading. Mol Cell. 2007; 26(4):523-37. DOI: 10.1016/j.molcel.2007.04.016. View

Midorikawa Y, Yamamoto S, Tsuji S, Kamimura N, Ishikawa S, Igarashi H . Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis. Hepatology. 2008; 49(2):513-22. DOI: 10.1002/hep.22698. View

Su H, Yang J, Xu T, Huang J, Xu L, Yuan Y . MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 2009; 69(3):1135-42. DOI: 10.1158/0008-5472.CAN-08-2886. View

Malumbres M, Barbacid M . Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009; 9(3):153-66. DOI: 10.1038/nrc2602. View

10.

Ponting C, Oliver P, Reik W . Evolution and functions of long noncoding RNAs. Cell. 2009; 136(4):629-41. DOI: 10.1016/j.cell.2009.02.006. View

11.

Xu T, Zhu Y, Xiong Y, Ge Y, Yun J, Zhuang S . MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology. 2009; 50(1):113-21. DOI: 10.1002/hep.22919. View

12.

Choe K, Ujhelly O, Wontakal S, Skoultchi A . PU.1 directly regulates cdk6 gene expression, linking the cell proliferation and differentiation programs in erythroid cells. J Biol Chem. 2009; 285(5):3044-52. PMC: 2823399. DOI: 10.1074/jbc.M109.077727. View

13.

Ding J, Huang S, Wu S, Zhao Y, Liang L, Yan M . Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA. Nat Cell Biol. 2010; 12(4):390-9. DOI: 10.1038/ncb2039. View

14.

Chen L, Chan T, Guan X . Chromosome 1q21 amplification and oncogenes in hepatocellular carcinoma. Acta Pharmacol Sin. 2010; 31(9):1165-71. PMC: 4002324. DOI: 10.1038/aps.2010.94. View

15.

Huo L, Wang Y, Xia W, Hsu S, Lai C, Li L . RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus. Proc Natl Acad Sci U S A. 2010; 107(37):16125-30. PMC: 2941329. DOI: 10.1073/pnas.1000743107. View

16.

Bohlig L, Friedrich M, Engeland K . p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins. Nucleic Acids Res. 2010; 39(2):440-53. PMC: 3025554. DOI: 10.1093/nar/gkq796. View

17.

Wang K, Chang H . Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011; 43(6):904-14. PMC: 3199020. DOI: 10.1016/j.molcel.2011.08.018. View

18.

Zhu Y, Lu Y, Zhang Q, Liu J, Li T, Yang J . MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. Nucleic Acids Res. 2012; 40(10):4615-25. PMC: 3378857. DOI: 10.1093/nar/gkr1278. View

19.

Karakatsanis A, Papaconstantinou I, Gazouli M, Lyberopoulou A, Polymeneas G, Voros D . Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog. 2012; 52(4):297-303. DOI: 10.1002/mc.21864. View

20.

Liu X, Li D, Zhang W, Guo M, Zhan Q . Long non-coding RNA gadd7 interacts with TDP-43 and regulates Cdk6 mRNA decay. EMBO J. 2012; 31(23):4415-27. PMC: 3512391. DOI: 10.1038/emboj.2012.292. View