G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis
| Autor: | Greg Kelly, Jason Sang Hun Lee, Michelle M. Hill, Fares Al-Ejeh, Thomas Stoll, Arabella Young, Mark J. Smyth, Frank Gannon, Donal J. Brennan, Francesco Casciello, Shin Foong Ngiow, Karolina Windloch |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Multidisciplinary GATA2 Regulator Gene signature Biology medicine.disease_cause 3. Good health ARNTL 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Gene expression Histone methylation medicine Cancer research Epigenetics Carcinogenesis |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:7077-7082 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome. This inefficiency leads to an increase in H3K9me2 at its target promoters. Blocking the methyltransferase activity of G9a inhibited cellular proliferation and migration in vitro and tumor growth in vivo. Furthermore, an increased level of G9a is a crucial factor in mediating the hypoxic response by down-regulating the expression of specific genes, including ARNTL, CEACAM7, GATA2, HHEX, KLRG1, and OGN. This down-regulation can be rescued by a small molecule inhibitor of G9a. Based on the hypothesis that the changes in gene expression would influence patient outcomes, we have developed a prognostic G9a-suppressed gene signature that can stratify breast cancer patients. Together, our findings provide an insight into the role G9a plays as an epigenetic mediator of hypoxic response, which can be used as a diagnostic marker, and proposes G9a as a therapeutic target for solid cancers. |
| Databáze: | OpenAIRE |
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