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| Status |
Public on Dec 20, 2017 |
| Title |
Inhibition of the H3K9 methyltransferase epigenetic regulator G9A attenuates oncogenicity but provokes a survival response via activation of the hypoxia pathway |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia-induced epigenetic changes may be key drivers of the adaptation of cancer cells to the hypoxic microenvironment typical of solid tumors. Previously, we showed that loss-of-function or inhibition of the oncogenic H3K9 methyltransferase G9A attenuates tumor growth and constitutes an important strategy for cancer management. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. Here, we show that G9A is highly expressed in breast cancer compared to normal breast tissue and is associated with poor prognosis in patients, where it may function as a potent oncogenic driver in this cancer type. In agreement with this, G9A inhibition leads to increased cell death, impaired cell migration, reduced cell cycle and downregulated anchorage-independent growth. Interestingly, whole transcriptome analysis revealed that a number of previously non-responsive genes become amenable to hypoxia following G9A inhibition, including many targets that drive cancer cell survival. This was accompanied by the upregulation of the hypoxia inducible factors HIF1A and HIF2A during the use of G9A inhibition to curb cancer cell growth even under normoxic conditions. Therefore, we show that G9A is a key mediator of oncogenic processes in breast cancer cells and cancer therapeutics involving G9A inhibition can be used successfully to attenuate oncogenicity. However, cancer cells mount a survival response via activation of the HIF pathway that may necessitate the additional suppression of HIF signaling for improved efficacy in the eradication of the disease.
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| Overall design |
27 samples consisting of MCF7 human breast cancer cells treated with 6 μM BIX-01294 in 0.1% dimethyl sulfoxide (DMSO) or 0.1% DMSO carrier controls and untreated controls in acute (4 hours) hypoxia, chronic (24 hours) hypoxia (1% O2) or normoxia (21% O2) control conditions in triplicate cultures.
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| Contributor(s) |
Ho JC, Ueda J, Pang QY, Kato H, Jha S, Yang H, Poellinger L, Lee KL |
| Citation(s) |
29145444 |
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| Submission date |
Nov 15, 2016 |
| Last update date |
Jun 13, 2019 |
| Contact name |
Kian Leong LEE |
| E-mail(s) |
kianleong.lee@duke-nus.edu.sg
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| Phone |
+(65) 6601 3685
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| Organization name |
National University of Singapore (NUS)
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| Department |
Duke-NUS Medical School
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| Lab |
Cancer & Stem Cell Biology Program (CSCB)
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| Street address |
#07-21, 8 College Road
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| City |
Singapore |
| State/province |
Singapore |
| ZIP/Postal code |
169857 |
| Country |
Singapore |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (27)
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| GSM2392640 |
MCF7 Normoxia No Treatment, Replicate 1 |
| GSM2392641 |
MCF7 Normoxia No Treatment, Replicate 2 |
| GSM2392642 |
MCF7 Normoxia No Treatment, Replicate 4 |
| GSM2392643 |
MCF7 Normoxia DMSO, Replicate 1 |
| GSM2392644 |
MCF7 Normoxia DMSO, Replicate 3 |
| GSM2392645 |
MCF7 Normoxia DMSO, Replicate 4 |
| GSM2392646 |
MCF7 Normoxia BIX, Replicate 1 |
| GSM2392647 |
MCF7 Normoxia BIX, Replicate 2 |
| GSM2392648 |
MCF7 Normoxia BIX, Replicate 4 |
| GSM2392649 |
MCF7 4h Hypoxia No Treatment, Replicate 2 |
| GSM2392650 |
MCF7 4h Hypoxia No Treatment, Replicate 3 |
| GSM2392651 |
MCF7 4h Hypoxia No Treatment, Replicate 4 |
| GSM2392652 |
MCF7 4h Hypoxia DMSO, Replicate 1 |
| GSM2392653 |
MCF7 4h Hypoxia DMSO, Replicate 3 |
| GSM2392654 |
MCF7 4h Hypoxia DMSO, Replicate 4 |
| GSM2392655 |
MCF7 4h Hypoxia BIX, Replicate 1 |
| GSM2392656 |
MCF7 4h Hypoxia BIX, Replicate 2 |
| GSM2392657 |
MCF7 4h Hypoxia BIX, Replicate 3 |
| GSM2392658 |
MCF7 24h Hypoxia No Treatment, Replicate 1 |
| GSM2392659 |
MCF7 24h Hypoxia No Treatment, Replicate 2 |
| GSM2392660 |
MCF7 24h Hypoxia No Treatment, Replicate 4 |
| GSM2392661 |
MCF7 24h Hypoxia DMSO, Replicate 1 |
| GSM2392662 |
MCF7 24h Hypoxia DMSO, Replicate 2 |
| GSM2392663 |
MCF7 24h Hypoxia DMSO, Replicate 4 |
| GSM2392664 |
MCF7 24h Hypoxia BIX, Replicate 1 |
| GSM2392665 |
MCF7 24h Hypoxia BIX, Replicate 2 |
| GSM2392666 |
MCF7 24h Hypoxia BIX, Replicate 4 |
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| Relations |
| BioProject |
PRJNA353654 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE89891_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| GSE89891_non-normalized.txt.gz |
7.9 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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