HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells

Ohe, Kenji; Miyajima, S.; Abe, Ichiro; Tanaka, Tomoko; Hamaguchi, Yukihisa; Harada, Yoshihiro; Horita, Yuta; Beppu, Yuki; Ito, Fumiaki; Yamasaki, Takafumi; Terai, Hiroki; Mori, Masayoshi; Murata, Yusuke; Tanabe, Makito; Ashida, Kenji; Kobayashi, Kazuo; Enjoji, Munechika; Yanase, Toshihiko; Harada, Nobuhiro; Utsumi, Toshiaki; Mayeda, Akila

doi:10.1016/j.jsbmb.2018.04.007

Cited by 20 publications

(26 citation statements)

References 35 publications

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“…The RNA transcribed from CDC-ERα includes the HMGA1a RNA-binding sequence in a shortened ERα exon1 with flanking intron sequences inserted in intron between CDC exon 14 and 15 (Figure 2A ). The splicing recapitulated that of cultured MCF-7 cells (Ohe et al, 2018 ), except that CDC-ERα showed exon skipping using HeLa nuclear extract in our in vitro splicing assay (Figure 2B , lane 2), thus we added SRSF1 and exon inclusion was observed (Figure 2B , lane 3). When HMGA1a was added to this reaction, an increase of exon exclusion was observed (Figure 2B , lane 4).…”

Section: Resultssupporting

confidence: 74%

“…Accordingly, we found a candidate HMGA1a RNA-binding site in the estrogen receptor alpha ( ER α) gene. It functioned in MCF-7 cells, induced estrogen-dependent growth in these cells as well as nude mice, and tamoxifen-resistant MCF-7 TAMR1 cells were sensitized to tamoxifen (Ohe et al, 2018 ). Here we show the in vitro analyses of HMGA1a-trapped U1 snRNP at the upstream pseudo 5′ splice site adjacent the HMGA1a RNA-binding site in ER α exon1, which is located downstream of several non-coding exons.…”

Section: Resultsmentioning

confidence: 99%

“…We believe that this induction of exon inclusion is significant in such limited exon inclusion conditions of this pre-mRNA substrate in vitro . The decoy effect of PS2 HMGA1a RNA-binding sequence was observed to inhibit alternative splicing induced by endogenous HMGA1a protein of MCF-7 cells (Ohe et al, 2018 ). Here we focus on HMGA1a-induced exon skipping of CDC-ERα and conducted further experiments to decipher the mechanism.…”

Section: Resultsmentioning

confidence: 99%

“…Estrogen receptor alpha (ERα) is an important biomarker as well as the key factor in estrogen-dependent growth of breast cancer. We have recently found that high-mobility group A protein 1a (HMGA1a) is involved in alternative splicing of ERα (Ohe et al, 2018 ). The resulting transcript, called ERα46 (Flouriot et al, 2000 ), is known for its function in partially inhibiting mitogenic activity of full length ERα (Penot et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

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HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5′ Splice Site

Ohe

Miyajima

Tanaka

et al. 2018

Front. Mol. Biosci.

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Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells.Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2′-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5′ splice site of exon 1.Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5′ splice site.Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5′ splice site of exon 1 offers novel insight on 5′ splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5′ Splice Site

Ohe

Miyajima

Tanaka

et al. 2018

Front. Mol. Biosci.

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“…ERα-46 is encoded by an ERα transcript that lacks the first exon of the ERα gene [ 79 ]. The high monility group A protein 1a (HMGA1a) induces alternative slicing of ERα thereby increasing ERα-46 expresison and reducing tamoxifen sensitivity in breast cancer cells [ 80 ]. Mechanistically, HMGA1 traps U1 snRNP at the 5′ splice site of exon 1 in ERα gene thereby inducing alternative splicing [ 81 ].…”

Section: Alternative Splicing Of Ermentioning

confidence: 99%

Mechanisms for estrogen receptor expression in human cancer

et al. 2018

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Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling and brain functions. However, estrogen also promotes mammary, ovarian and endometrial tumorigenesis. Estrogen antagonists and drugs that reduce estrogen biosynthesis have become highly successful therapeutic agents for breast cancer patients. The effects of estrogen are largely mediated by estrogen receptor (ER) α and ERβ, which are members of the nuclear receptor superfamily of transcription factors. The mechanisms underlying the aberrant expression of ER in breast cancer and other types of human tumors are complex, involving considerable alternative splicing of ERα and ERβ, transcription factors, epigenetic and post-transcriptional regulation of ER expression. Elucidation of mechanisms for ER expression may not only help understand cancer progression and evolution, but also shed light on overcoming endocrine therapy resistance. Herein, we review the complex mechanisms for regulating ER expression in human cancer.

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The synergy between miR-486–5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells

Mansoori

Najafi

Mohammadi

et al. 2021

Biomedicine & Pharmacotherapy

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HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells

Cited by 20 publications

References 35 publications

HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5′ Splice Site

HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5′ Splice Site

Mechanisms for estrogen receptor expression in human cancer

The synergy between miR-486–5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells

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