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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Published in:Breast cancer research : BCR Vol. 21; no. 1; pp. 47 - 17
Main Authors: Cairns, Junmei, Ingle, James N., Kalari, Krishna R., Shepherd, Lois E., Kubo, Michiaki, Goetz, Matthew P., Weinshilboum, Richard M., Wang, Liewei
Format: Journal Article
Language:English
Published: London BioMed Central 03.04.2019
Springer Nature B.V
BMC
Subjects:
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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Summary: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.
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ISSN:1465-542X
1465-5411
1465-542X
DOI:10.1186/s13058-019-1130-3