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Lnc‐UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9‐Mediated CDK6 Down‐regulation
- Source :
- Hepatology (Baltimore, Md.)
- Publication Year :
- 2019
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2019.
-
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.
- Subjects :
- 0301 basic medicine
Small interfering RNA
Carcinoma, Hepatocellular
DEAD-box RNA Helicases
Mice
03 medical and health sciences
0302 clinical medicine
Animals
Humans
Hepatobiliary Malignancies
Hepatology
biology
Cell growth
Chemistry
Cell Cycle
Liver Neoplasms
HEK 293 cells
RNA
G1/S transition
Cyclin-Dependent Kinase 6
Hep G2 Cells
Original Articles
Cell cycle
RNA Helicase A
Neoplasm Proteins
MicroRNAs
HEK293 Cells
030104 developmental biology
Cancer research
biology.protein
RNA, Long Noncoding
Original Article
030211 gastroenterology & hepatology
Cyclin-dependent kinase 6
Subjects
Details
- ISSN :
- 15273350 and 02709139
- Volume :
- 70
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....45a5bddb11b2829913082de1bb44a762