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On-line Access: 2021-12-14

Received: 2021-04-27

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 ORCID:

Li TAN

https://orcid.org/0000-0001-5961-0450

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Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.12 P.1034-1044

http://doi.org/10.1631/jzus.B2100393


ERα promotes transcription of tumor suppressor gene ApoA-I by establishing H3K27ac-enriched chromatin microenvironment in breast cancer cells


Author(s):  Bingjie WANG, Yinghui SHEN, Tianyu LIU, Li TAN

Affiliation(s):  Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; more

Corresponding email(s):   litan@fudan.edu.cn

Key Words:  Apolipoprotein A-I (ApoA-I), Estrogen receptor α, (ERα, ), Acetylation of histone 3 lysine 27 (H3K27ac), p300, Breast cancer


Bingjie WANG, Yinghui SHEN, Tianyu LIU, Li TAN. ERα promotes transcription of tumor suppressor gene ApoA-I by establishing H3K27ac-enriched chromatin microenvironment in breast cancer cells[J]. Journal of Zhejiang University Science B, 2021, 22(12): 1034-1044.

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author="Bingjie WANG, Yinghui SHEN, Tianyu LIU, Li TAN",
journal="Journal of Zhejiang University Science B",
volume="22",
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publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2100393"
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%T ERα promotes transcription of tumor suppressor gene ApoA-I by establishing H3K27ac-enriched chromatin microenvironment in breast cancer cells
%A Bingjie WANG
%A Yinghui SHEN
%A Tianyu LIU
%A Li TAN
%J Journal of Zhejiang University SCIENCE B
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%DOI 10.1631/jzus.B2100393

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T1 - ERα promotes transcription of tumor suppressor gene ApoA-I by establishing H3K27ac-enriched chromatin microenvironment in breast cancer cells
A1 - Bingjie WANG
A1 - Yinghui SHEN
A1 - Tianyu LIU
A1 - Li TAN
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 12
SP - 1034
EP - 1044
%@ 1673-1581
Y1 - 2021
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2100393


Abstract: 
)%29&ck%5B%5D=abstract&ck%5B%5D=keyword'>apolipoprotein A-I (ApoA-I), the main protein component of high-density lipoprotein (HDL), plays a pivotal role in reverse cholesterol transport (RCT). Previous studies indicated a reduction of serum ApoA-I levels in various types of cancer, suggesting ApoA-I as a potential cancer biomarker. Herein, ectopically overexpressed ApoA-I in MDA-MB-231 breast cancer cells was observed to have antitumor effects, inhibiting cell proliferation and migration. Subsequent studies on the mechanism of expression regulation revealed that estradiol (E2)/estrogen receptor α; (ERα;) signaling activates ApoA-I gene transcription in breast cancer cells. Mechanistically, our ChIP-seq data showed that ERα directly binds to the estrogen response element (ERE) site within the ApoA-I gene and establishes an acetylation of histone 3 lysine 27 (H3K27ac)‍-enriched chromatin microenvironment. Conversely, Fulvestrant (ICI 182780) treatment blocked ERαbinding to ERE within the ApoA-I gene and downregulated the H3K27ac level on the ApoA-I gene. Treatment with p300 inhibitor also significantly decreased the ApoA-I messenger RNA (mRNA) level in MCF7 cells. Furthermore, the analysis of data from The Cancer Genome Atlas (TCGA) revealed a positive correlation between ERα and ApoA-I expression in breast cancer tissues. Taken together, our study not only revealed the antitumor potential of ApoA-I at the cellular level, but also found that ERα promotes the transcription of ApoA-I gene through direct genomic effects, and p300 may act as a co-activator of ERα in this process.

ERα通过在乳腺癌细胞中建立富含H3K27ac修饰的染色质微环境促进抑癌基因ApoA-I的转录

目的:载脂蛋白A-I(apolipoproteinA-I,ApoA-I)是高密度脂蛋白的主要蛋白成分。已有研究表明ApoA-I除了参与胆固醇逆转运,还能够抑制炎症反应以及抑制肿瘤的生长、侵袭和代谢活动。另外,多种癌症病人的血清中ApoA-I的水平相较健康人是降低的。ApoA-I作为潜在的抗肿瘤因子具有重要的研究价值。本研究旨在探究ApoA-I对乳腺癌细胞生物学行为的影响以及对乳腺癌发生发展起重要作用的雌激素/雌激素受体(E2/ERα)信号通路是否参与了ApoA-I的表达调控。
创新点:本研究在细胞层面上证明了ApoA-I具有抑癌功能,另外结合体外实验以及TCGA数据分析,首次发现乳腺癌细胞中ApoA-I是ERα的直接靶基因,这为理解ERα在乳腺癌中的双刃剑作用提供了新的切入点。同时,我们猜测雌激素替代疗法联合ApoA-I模拟肽给药可能会增强luminal(ERα表达阳性)型乳腺癌的治疗效果。
方法:通过干预E2/ERα信号通路(用雌激素受体拮抗剂ICI182780降解ERα;激素剥夺后加入E2激活E2/ERα信号通路;在三阴性乳腺癌细胞MDA-MB-231中过表达ERα),观察ApoA-I转录水平的变化;通过用ERα抗体进行ChIP-seq结合序列分析探究ERα是否直接调控ApoA-I转录;在激素剥夺或ICI182780处理的条件下用组蛋白H3赖氨酸27位点乙酰化(H3K27ac)抗体进行ChIP-seq或ChIP-qPCR,结合乙酰转移酶p300抑制剂处理,探究ERα调控ApoA-I转录的具体机制。
结论:ERα能够直接结合在ApoA-I基因的最后一个外显子上促进ApoA-I的转录,且该结合位点上有一个雌激素响应元件(ERE);p300可能作为ERα的一个共激活因子,通过建立富含H3K27ac的染色质微环境来激活ApoA-I的转录。

关键词:载脂蛋白A-I(ApoA-I);ERα;组蛋白H3赖氨酸27位点乙酰化(H3K27ac);乙酰转移酶p300;乳腺癌

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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