Targeting long non-coding RNA ASBEL with oligonucleotide antagonist for breast cancer therapy.

Long non-coding RNAs (lncRNAs) are defined as a class of RNA transcripts longer than 200 nucleotides encoded by mammalian genomes that lack protein-coding potential. LncRNA ASBEL has been identified as an anti-sense transcript of BTG3 (B cell translocation gene 3) gene, which encodes an anti-proliferation protein. Remarkable down-regulation of BTG3 has been reported in triple-negative breast cancer (TNBC). In the present study, a number of single-stranded modified anti-sense DNA oligonucleotides (antago) were designed, synthesized and screened for specific lncRNA ASBEL knockdown. We showed here that anti-ASBEL antago played a significant tumor suppressive role in TNBC by effective down-regulating lncRNA ASBEL, which in turn led to increased BTG3 expression. The obtained data suggest lncRNA ASBEL as a novel therapeutic target in TNBC.

[1]  D. Patterson,et al.  Methylation-mediated downregulation of the B-cell translocation gene 3 (BTG3) in breast cancer cells. , 2008, Gene expression.

[2]  A. Okamoto,et al.  ASBEL, an ANA/BTG3 antisense transcript required for tumorigenicity of ovarian carcinoma , 2013, Scientific Reports.

[3]  Poul Nielsen,et al.  LNA (Locked Nucleic Acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition , 1998 .

[4]  Howard Y. Chang,et al.  Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes , 2010, Science.

[5]  Masaharu Kataoka,et al.  Non-Coding RNAs Including miRNAs and lncRNAs in Cardiovascular Biology and Disease , 2014, Cells.

[6]  K. Shinozuka,et al.  Physicochemical properties of phosphorothioate oligodeoxynucleotides. , 1988, Nucleic acids research.

[7]  Sarah L. DeVos,et al.  Antisense Oligonucleotides: Treating Neurodegeneration at the Level of RNA , 2013, Neurotherapeutics.

[8]  T. Morgan,et al.  Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase , 2008, Nature Medicine.

[9]  Yanqing Ding,et al.  The Suppressive Role and Aberrent Promoter Methylation of BTG3 in the Progression of Hepatocellular Carcinoma , 2013, PloS one.

[10]  L. Stanton,et al.  Long noncoding RNAs in development and disease of the central nervous system. , 2013, Trends in genetics : TIG.

[11]  W. F. Lima,et al.  Human RNases H. , 2001, Methods in enzymology.

[12]  J. Vaughn,et al.  RNA editing and regulation of Drosophila 4f-rnp expression by sas-10 antisense readthrough mRNA transcripts. , 2003, RNA.

[13]  Brian S. Clark,et al.  The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. , 2006, Genes & development.

[14]  Michael Thomas,et al.  MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer , 2003, Oncogene.

[15]  Irmtraud M. Meyer,et al.  The clonal and mutational evolution spectrum of primary triple-negative breast cancers , 2012, Nature.

[16]  R. Dahiya,et al.  BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. , 2009, Carcinogenesis.

[17]  E. Castanas,et al.  Natural antisense RNA inhibits the expression of BCMA, a tumour necrosis factor receptor homologue. , 2002, BMC Molecular Biology.

[18]  D. Witchell,et al.  Short antisense oligonucleotides with novel 2'-4' conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals. , 2009, Journal of medicinal chemistry.

[19]  M. Esteller Non-coding RNAs in human disease , 2011, Nature Reviews Genetics.

[20]  Sidong Wei,et al.  Downregulation of BTG3 in non-small cell lung cancer. , 2013, Biochemical and biophysical research communications.

[21]  K. Shirahige,et al.  ASBEL–TCF3 complex is required for the tumorigenicity of colorectal cancer cells , 2016, Proceedings of the National Academy of Sciences.

[22]  A. Wierzbicki,et al.  A SWI/SNF Chromatin-Remodeling Complex Acts in Noncoding RNA-Mediated Transcriptional Silencing , 2013, Molecular cell.

[23]  R. Dahiya,et al.  Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B‐Cell translocation gene 3 in prostate cancer , 2009, Cancer.

[24]  Yan Wang,et al.  Long non-coding RNAs: versatile master regulators of gene expression and crucial players in cancer. , 2012, American journal of translational research.

[25]  B. Blencowe,et al.  The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. , 2010, Molecular cell.

[26]  Maite Huarte The emerging role of lncRNAs in cancer , 2015, Nature Medicine.

[27]  A. Fatica,et al.  Long non-coding RNAs: new players in cell differentiation and development , 2013, Nature Reviews Genetics.