SLCO4A1-AS1 promotes colorectal tumourigenesis by regulating Cdk2/c-Myc signalling

Background SLCO4A1-AS1 was found to be upregulated in several cancer types, including colorectal cancer (CRC). However, the detailed roles of SLCO4A1-AS1 in CRC remain to be elucidated. Therefore, we investigated the functions, mechanism, and clinical significance of SLCO4A1-AS1 in colorectal tumour...

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Veröffentlicht in:Journal of biomedical science Jg. 29; H. 1; S. 4 - 17
Hauptverfasser: Zhang, Jia, Cui, Kaisa, Huang, Liuying, Yang, Fan, Sun, Shengbai, Bian, Zehua, Wang, Xue, Li, Chaoqun, Yin, Yuan, Huang, Shengling, Zhou, Leyuan, Fei, Bojian, Huang, Zhaohui
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BioMed Central 17.01.2022
BioMed Central Ltd
Springer Nature B.V
BMC
Schlagworte:
Analysis
Antibodies
Biomedical and Life Sciences
Biomedicine
c-Myc
c-Myc protein
Cancer
Carcinogenesis - genetics
Cdk2
Cell cycle
Cell growth
Cell Line, Tumor
Cell Movement
Cell Proliferation - genetics
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Cyclin-Dependent Kinase 2
DNA methylation
Gene Expression Regulation, Neoplastic
Genes
Heat shock proteins
Hsp90 protein
Humans
Immunohistochemistry
Immunoprecipitation
In vivo methods and tests
Long non-coding RNA
Mass spectrometry
Metastasis
Methylation
MicroRNAs
Myc protein
Pathogenesis
Phosphorylation
Plasmids
Prognosis
Proteins
Proto-Oncogene Proteins c-myc
Ribonucleic acid
RNA
RNA, Antisense
RNA, Long Noncoding
Scientific imaging
Signal transduction
Signal Transduction - genetics
Signaling
SLCO4A1-AS1
Therapeutic targets
Tumorigenesis
Tumors
China
United States > US
SLCO4A1-AS1
c-Myc
Colorectal cancer
Cdk2
Long non-coding RNA
ISSN:1423-0127, 1021-7770, 1423-0127
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Zusammenfassung:Background SLCO4A1-AS1 was found to be upregulated in several cancer types, including colorectal cancer (CRC). However, the detailed roles of SLCO4A1-AS1 in CRC remain to be elucidated. Therefore, we investigated the functions, mechanism, and clinical significance of SLCO4A1-AS1 in colorectal tumourigenesis. Methods We measured the expression of SLCO4A1-AS1 in CRC tissues using qRT-PCR and determined its correlation with patient prognosis. Promoter methylation analyses were used to assess the methylation status of SLCO4A1-AS1. Gain- and loss-of-function assays were used to evaluate the effects of SLCO4A1-AS1 on CRC growth in vitro and in vivo. RNA pull-down, RNA immunoprecipitation, RNA-seq, luciferase reporter and immunohistochemistry assays were performed to identify the molecular mechanism of SLCO4A1-AS1 in CRC. Results SLCO4A1-AS1 was frequently upregulated in CRC tissues based on multiple CRC cohorts and was associated with poor prognoses. Aberrant overexpression of SLCO4A1-AS1 in CRC is partly attributed to the DNA hypomethylation of its promoter. Ectopic SLCO4A1-AS1 expression promoted CRC cell growth, whereas SLCO4A1-AS1 knockdown repressed CRC proliferation both in vitro and in vivo. Mechanistic investigations revealed that SLCO4A1-AS1 functions as a molecular scaffold to strengthen the interaction between Hsp90 and Cdk2, promoting the protein stability of Cdk2. The SLCO4A1-AS1-induced increase in Cdk2 levels activates the c-Myc signalling pathway by promoting the phosphorylation of c-Myc at Ser62, resulting in increased tumour growth. Conclusions Our data demonstrate that SLCO4A1-AS1 acts as an oncogene in CRC by regulating the Hsp90/Cdk2/c-Myc axis, supporting SLCO4A1-AS1 as a potential therapeutic target and prognostic factor for CRC.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1423-0127
1021-7770
1423-0127
DOI:10.1186/s12929-022-00789-z