Dataset Information

The Role of APAL/ST8SIA6-AS1 lncRNA in PLK1 Activation and Mitotic Catastrophe of Tumor Cells.

ABSTRACT: Background:Tumor growth can be addicted to vital oncogenes, but whether long noncoding RNAs (lncRNAs) are essential to cancer survival is largely uncharacterized.

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.

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?
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.

SUBMITTER: Luo ML

PROVIDER: S-EPMC7156940 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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The Role of APAL/ST8SIA6-AS1 lncRNA in PLK1 Activation and Mitotic Catastrophe of Tumor Cells.

Luo Man-Li ML Li Jingjing J Shen Liping L Chu Junjun J Guo Qiannan Q Liang Guorun G Wu Wei W Chen Jianing J Chen Rufu R Song Erwei E

Journal of the National Cancer Institute 20200401 4

<h4>Background</h4>Tumor growth can be addicted to vital oncogenes, but whether long noncoding RNAs (lncRNAs) are essential to cancer survival is largely uncharacterized.<h4>Methods</h4>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 ...[more]

PMID: 31286138

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Project description:BackgroundKRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies.MethodsBy using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo.ResultsKRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance.ConclusionsOur study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.

Dataset Information

The Role of APAL/ST8SIA6-AS1 lncRNA in PLK1 Activation and Mitotic Catastrophe of Tumor Cells.

Publications

The Role of APAL/ST8SIA6-AS1 lncRNA in PLK1 Activation and Mitotic Catastrophe of Tumor Cells.

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