Abstract
BackgroundOur 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.MethodsRNA-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.ResultsMIR2052HG 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.ConclusionsOur 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.
Highlights
Our previous genome-wide association study using the MA.27 aromatase inhibitors adjuvant trial identified Single-nucleotide polymorphisms (SNP) in the long noncoding RNA MIR2052HG associated with breast cancer-free interval
MIR2052HG regulates lemur tyrosine kinase-3 (LMTK3) expression We previously reported that MIR2052HG sustained estrogen receptor α (ERα) levels by promoting AKT/FOXO3-mediated upregulation of ESR1 transcript and by limiting proteasome-dependent degradation of ERα protein [28]
Given that the effects of LMTK3 on ERα were similar to our observations with MIR2052HG [28], we hypothesized that MIR2052HG might regulate LMTK3 to mediate ERα levels and, in turn, response to Aromatase inhibitor (AI)
Summary
Our previous genome-wide association study using the MA. aromatase inhibitors adjuvant trial identified SNPs in the long noncoding RNA MIR2052HG associated with breast cancer-free interval. 70% of breast cancers are ERα positive and rely on estrogen signaling to stimulate their growth and survival [1, 2]. The third-generation AIs (i.e., exemestane, anastrozole, and letrozole) have largely replaced tamoxifen as the preferred treatment for ERα-positive breast cancer in postmenopausal women with early-stage breast cancer because of their superior efficacy over tamoxifen [3, 4]. Both de novo and acquired resistance to AIs can occur, resulting in relapse and disease progression. The mechanisms for endocrine therapy resistance are complex and one mechanism includes dysregulation of ERα expression, encoded by ESR1 [8]
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