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The Role of APAL/ST8SIA6-AS1 lncRNA in PLK1 Activation and Mitotic Catastrophe of Tumor Cells.
- Source :
-
Journal of the National Cancer Institute [J Natl Cancer Inst] 2020 Apr 01; Vol. 112 (4), pp. 356-368. - Publication Year :
- 2020
-
Abstract
- Background: Tumor growth can be addicted to vital oncogenes, but whether long noncoding RNAs (lncRNAs) are essential to cancer survival is largely uncharacterized.<br />Methods: We retrieved Gene Expression Omnibus datasets to identify lncRNA overexpression in 257 cancers vs 196 normal tissues and analyzed the association of ST8SIA6-AS1 (termed Aurora A/Polo-like-kinase 1 [PLK1]-associated lncRNA, APAL) with the clinical outcomes of multiple types of cancer from public RNA sequencing and microarray datasets as well as from in-house cancer cohorts. Loss- and gain-of-function experiments were performed to explore the role of APAL in cancers in vitro and in vivo. RNA pulldown and RNA immunoprecipitation were used to investigate APAL-interacting proteins. All statistical tests were two-sided.<br />Results: APAL is overexpressed in multiple human cancers associated with poor clinical outcome of patients. APAL knockdown causes mitotic catastrophe and massive apoptosis in human breast, lung, and pancreatic cancer cells. Overexpressing APAL accelerates cancer cell cycle progression, promotes proliferation, and inhibits chemotherapy-induced apoptosis. Mechanism studies show that APAL links up PLK1 and Aurora A to enhance Aurora A-mediated PLK1 phosphorylation. Notably, targeting APAL inhibits the growth of breast and lung cancer xenografts in vivo (MCF-7 xenografts: mean tumor weight, control = 0.18 g [SD = 0.03] vs APAL locked nucleic acids = 0.07 g [SD = 0.02], P < .001, n = 8 mice per group; A549 xenografts: mean tumor weight control = 0.36 g [SD = 0.10] vs APAL locked nucleic acids = 0.10 g [SD = 0.04], P < .001, n = 9 mice per group) and the survival of patient-derived breast cancer organoids in three-dimensional cultures.<br />Conclusions: Our data highlight the essential role of lncRNA in cancer cell survival and the potential of APAL as an attractive therapeutic target for a broad-spectrum of cancers.<br /> (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- A549 Cells
Animals
Aurora Kinase A genetics
Aurora Kinase A metabolism
Cell Cycle Proteins genetics
Heterografts
Humans
MCF-7 Cells
Mice
Mice, Nude
Mitosis physiology
Neoplasms pathology
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Proteins genetics
RNA, Antisense genetics
RNA, Long Noncoding genetics
Polo-Like Kinase 1
Cell Cycle Proteins metabolism
Neoplasms genetics
Neoplasms metabolism
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins metabolism
RNA, Long Noncoding metabolism
Sialyltransferases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2105
- Volume :
- 112
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 31286138
- Full Text :
- https://doi.org/10.1093/jnci/djz134