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Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11661-E11670. doi: 10.1073/pnas.1805950115. Epub 2018 Nov 26.

Dual functions for OVAAL in initiation of RAF/MEK/ERK prosurvival signals and evasion of p27-mediated cellular senescence.

Author information

1
Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Cell and Molecular Biology, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
2
Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Science, Zhengzhou University, 450003 Zhengzhou, China.
3
School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW 2308, Australia.
4
Department of Molecular Biology, Shanxi Cancer Hospital and Institute, 030013 Taiyuan, Shanxi, China.
5
Department of Pathology, Shanxi Cancer Hospital and Institute, 030013 Taiyuan, Shanxi, China.
6
School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
7
School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia.
8
School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW 2308, Australia; lei.jin@newcastle.edu.au wumian@ustc.edu.cn.
9
Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Cell and Molecular Biology, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China; lei.jin@newcastle.edu.au wumian@ustc.edu.cn.

Abstract

Long noncoding RNAs (lncRNAs) function through a diverse array of mechanisms that are not presently fully understood. Here, we sought to find lncRNAs differentially regulated in cancer cells resistant to either TNF-related apoptosis-inducing ligand (TRAIL) or the Mcl-1 inhibitor UMI-77, agents that act through the extrinsic and intrinsic apoptotic pathways, respectively. This work identified a commonly up-regulated lncRNA, ovarian adenocarcinoma-amplified lncRNA (OVAAL), that conferred apoptotic resistance in multiple cancer types. Analysis of clinical samples revealed OVAAL expression was significantly increased in colorectal cancers and melanoma in comparison to the corresponding normal tissues. Functional investigations showed that OVAAL depletion significantly inhibited cancer cell proliferation and retarded tumor xenograft growth. Mechanically, OVAAL physically interacted with serine/threonine-protein kinase 3 (STK3), which, in turn, enhanced the binding between STK3 and Raf-1. The ternary complex OVAAL/STK3/Raf-1 enhanced the activation of the RAF protooncogene serine/threonine-protein kinase (RAF)/mitogen-activated protein kinase kinase 1 (MEK)/ERK signaling cascade, thus promoting c-Myc-mediated cell proliferation and Mcl-1-mediated cell survival. On the other hand, depletion of OVAAL triggered cellular senescence through polypyrimidine tract-binding protein 1 (PTBP1)-mediated p27 expression, which was regulated by competitive binding between OVAAL and p27 mRNA to PTBP1. Additionally, c-Myc was demonstrated to drive OVAAL transcription, indicating a positive feedback loop between c-Myc and OVAAL in controlling tumor growth. Taken together, these results reveal that OVAAL contributes to the survival of cancer cells through dual mechanisms controlling RAF/MEK/ERK signaling and p27-mediated cell senescence.

KEYWORDS:

OVAAL; c-Myc; p27; proliferation; senescence

PMID:
30478051
PMCID:
PMC6294934
DOI:
10.1073/pnas.1805950115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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