Inhibition of the H3K9 methyltransferase G9A attenuates oncogenicity and activates the hypoxia signaling pathway

• Published in: PloS one 2017-11, Vol.12 (11), p.e0188051-e0188051
• Main Authors: Ho, Jolene Caifeng, Abdullah, Lissa Nurrul, Pang, Qing You, Jha, Sudhakar, Chow, Edward Kai-Hua, Yang, Henry, Kato, Hiroyuki, Poellinger, Lorenz, Ueda, Jun, Lee, Kian Leong
• Format: Article
• Language: English
• Subjects: Adaptation; Angiogenesis; Apoptosis; Attenuation; Biology; Biology and Life Sciences; Breast cancer; Cancer; Cancer therapies; Cell cycle; Cell death; Cell growth; Cell migration; Cervical cancer; Epigenetics; Gene expression; Genes; Genetic aspects; Genomics; Hypoxia; Inhibition; Kinases; Leukocyte migration; Management; Medical screening; Medicin och hälsovetenskap; Medicine and Health Sciences; Methyltransferase; Methyltransferases; Physiological aspects; Proteins; Signal transduction; Signaling; Solid tumors; Stem cells; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0188051

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 HIF1α and HIF2α 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.