期刊
PLOS ONE
卷 12, 期 11, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0188051
关键词
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资金
- National University Cancer Institute, Singapore (NCIS) [NR13NMR1340M]
- National Medical Research Council (NM RC) Clinician Scientist Individual Research Grant (CS-IRG) [NMRC/CIRG/1389/2014]
- National Research Foundation (NRF) Singapore
- Singapore Ministry of Education (MOE) under the Research Centres of Excellence initiative [R-713-005-014-271, R-713-010-189-112]
- Ministry of Education, Singapore AcRF [MOE2015-T2-2-126]
- Cancer Science Institute of Singapore RCE
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI [JP16K07099, JP16H01319]
- Swedish Research Council
Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia- induced epigenetic changes may be critical for the adaptation of cancer cells to the hypoxic microenvironment of solid tumors. Previously, we showed that loss-of-function of the hypoxia-regulated H3K9 methyltransferase G9A attenuates tumor growth. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. We show that G9A is highly expressed in breast cancer and is associated with poor patient prognosis, where it may function as a potent oncogenic driver. In agreement with this, G9A inhibition by the small molecule inhibitor, BIX-01294, leads to increased cell death and impaired cell migration, cell cycle and anchorage-independent growth. Interestingly, whole transcriptome analysis revealed that genes involved in diverse cancer cell functions become hypoxia-responsive upon G9A inhibition. This was accompanied by the upregulation of the hypoxia inducible factors HIF1 alpha and HIF2 alpha during BIX-01294 treatment even in normoxia that may facilitate the tumor suppressive effects of BIX-01294. HIF inhibition was able to reverse some of the transcriptional changes induced by BIX-01294 in hypoxia, indicating that the HIFs may be important drivers of these derepressed target genes. Therefore, we show that G9A is a key mediator of oncogenic processes in breast cancer cells and G9A inhibition by BIX-01294 can successfully attenuate oncogenicity even in hypoxia.
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