G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis

Casciello, Francesco, Al-Ejeh, Fares, Kelly, Greg, Brennan, Donal J., Ngiow, Shin Foong, Young, Arabella, Stoll, Thomas, Windloch, Karolina, Hill, Michelle M., Smyth, Mark J., Gannon, Frank and Lee, Jason S. (2017) G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis. Proceedings of the National Academy of Sciences, 114 27: 7077-7082. doi:10.1073/pnas.1618706114


Author Casciello, Francesco
Al-Ejeh, Fares
Kelly, Greg
Brennan, Donal J.
Ngiow, Shin Foong
Young, Arabella
Stoll, Thomas
Windloch, Karolina
Hill, Michelle M.
Smyth, Mark J.
Gannon, Frank
Lee, Jason S.
Title G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis
Journal name Proceedings of the National Academy of Sciences   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2017-07-03
Sub-type Article (original research)
DOI 10.1073/pnas.1618706114
Open Access Status Not yet assessed
Volume 114
Issue 27
Start page 7077
End page 7082
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Subject 1000 General
Abstract 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.
Formatted abstract
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.
Keyword Breast cancer
G9a
Histone methylation
Hypoxia
Epigenetics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 2009-0045833
Institutional Status UQ

 
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