G9a histone methyltransferase: a link between epigenetic regulation and tumour hypoxia in breast cancer

7^th World Congress on Breast Cancer

May 10-11, 2018 | Frankfurt, Germany

Francesco Casciello, Fares Al Ejeh, Greg Kelly, Donal J Brennan, Shin Foong Ngiow, Arabella Young, Thomas Stoll, Michelle M Hill, Mark J Smyth, Frank Gannon and Jason S Lee

QIMR Berghofer Medical Research Institute, Australia
Queensland University of Technology, Australia
MMUH - UCD School of Medicine, Ireland
University of Queensland, Australia
Diamantina Institute - University of Queensland, Australia
Translational Research Institute, Australia

Posters & Accepted Abstracts: J Cancer Sci Ther

Abstract :

G9a is an epigenetic regulator that methylates H3K9 generally causing repression of gene expression and participate in diverse cellular functions. G9a is genetically deregulated in a variety of tumour-types, and can silence tumour suppressor genes and therefore is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumour 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 leads to an increase in H3K9me2 at its target promoters. Blocking the methyltransferase activity of G9a inhibited cellular proliferation and migration in vitro and tumour 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 a new 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.