The lncRNA MIR2052HG regulates ERα levels and aromatase inhibitor resistance through LMTK3 by recruiting EGR1

Background Our previous genome-wide association study using the MA.27 aromatase inhibitors adjuvant trial identified SNPs in the long noncoding RNA MIR2052HG associated with breast cancer-free interval. MIR2052HG maintained ERα both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting...

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Vydáno v:	Breast cancer research : BCR Ročník 21; číslo 1; s. 47 - 17
Hlavní autoři:	Cairns, Junmei, Ingle, James N., Kalari, Krishna R., Shepherd, Lois E., Kubo, Michiaki, Goetz, Matthew P., Weinshilboum, Richard M., Wang, Liewei
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 03.04.2019 Springer Nature B.V BMC
Témata:	AKT protein Androstenedione Aromatase Aromatase Inhibitors - pharmacology Binding sites Biomarkers Biomedical and Life Sciences Biomedicine Breast cancer Cancer Research Cell Line, Tumor Cell Proliferation Cell Survival - genetics Chromatin Drug Resistance, Neoplasm - genetics Early Growth Response Protein 1 - genetics Early Growth Response Protein 1 - metabolism EGR-1 protein EGR1 Endocrine therapy ERα ESR1 protein Estrogen Receptor alpha - genetics Estrogen Receptor alpha - metabolism Estrogens Extracellular signal-regulated kinase Female Fluorescence in situ hybridization FOXO3 protein Gene expression Genome-wide association studies Genomes Humans Immunoprecipitation Kinases Ligands LMTK3 Localization Lon noncoding RNA Lymphoblastoid cell lines Medical prognosis Membrane Proteins - genetics Membrane Proteins - metabolism MIR2052HG Models, Biological Oncology Phosphorylation PKC Polymorphism, Single Nucleotide Protein kinase C Protein Stability Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Protein-tyrosine kinase Proteins Research Article Ribonucleic acid Ribosomal protein S6 kinase RNA RNA, Long Noncoding - genetics RNA-binding protein Signal Transduction Single-nucleotide polymorphism Surgical Oncology Transcription factors Transcription, Genetic Tumors Ubiquitin EGR1 Aromatase inhibitor ERα LMTK3 MIR2052HG PKC Lon noncoding RNA
ISSN:	1465-542X, 1465-5411, 1465-542X
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Shrnutí:	Background Our previous genome-wide association study using the MA.27 aromatase inhibitors adjuvant trial identified SNPs in the long noncoding RNA MIR2052HG associated with breast cancer-free interval. MIR2052HG maintained ERα both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated ERα degradation. Our goal was to further elucidate MIR2052HG’s mechanism of action. Methods RNA-binding protein immunoprecipitation assays were performed to demonstrate that the transcription factor, early growth response protein 1 (EGR1), worked together with MIR2052HG to regulate that lemur tyrosine kinase-3 (LMTK3) transcription in MCF7/AC1 and CAMA-1 cells. The location of EGR1 on the LMTK3 gene locus was mapped using chromatin immunoprecipitation assays. The co-localization of MIR2052HG RNA and the LMTK3 gene locus was determined using RNA-DNA dual fluorescent in situ hybridization. Single-nucleotide polymorphisms (SNP) effects were evaluated using a panel of human lymphoblastoid cell lines. Results MIR2052HG depletion in breast cancer cells results in a decrease in LMTK3 expression and cell growth. Mechanistically, MIR2052HG interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter. LMTK3 sustains ERα levels by reducing protein kinase C (PKC) activity, resulting in increased ESR1 transcription mediated through AKT/FOXO3 and reduced ERα degradation mediated by the PKC/MEK/ERK/RSK1 pathway. MIR2052HG regulated LMTK3 in a SNP- and aromatase inhibitor-dependent fashion: the variant SNP increased EGR1 binding to LMTK3 promoter in response to androstenedione, relative to wild-type genotype, a pattern that can be reversed by aromatase inhibitor treatment. Finally, LMTK3 overexpression abolished the effect of MIR2052HG on PKC activity and ERα levels. Conclusions Our findings support a model in which the MIR2052HG regulates LMTK3 via EGR1, and LMTK3 regulates ERα stability via the PKC/MEK/ERK/RSK1 axis. These results reveal a direct role of MIR2052HG in LMTK3 regulation and raise the possibilities of targeting MIR2052HG or LMTK3 in ERα-positive breast cancer.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1465-542X 1465-5411 1465-542X
DOI:	10.1186/s13058-019-1130-3