Article
Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis Cancer Research 82 (7) canres.2218.2021-1221 https://doi.org/10.1158/0008-5472.can-21-2218
Authors
Casciello, Francesco, Kelly, Gregory M., Ramarao-Milne, Priya, Kamal, Nabilah, Stewart, Teneale A., Mukhopadhyay, Pamela, Kazakoff, Stephen H., Miranda, Mariska, Kim, Dorim, Davis, Felicity M., Hayward, Nicholas K., Vertino, Paula M., Waddell, Nicola, Gannon, Frank, and Lee, Jason S.
Affiliations
QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Biomedical Sciences, Queensland University of Technology, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. Faculty of Medicine, Mater Research Institute The University of Queensland, Woolloongabba, Queensland, Australia. Translational Research Institute, Woolloongabba, Queensland, Australia. EMBL Australia Node in Single Molecule Science, School of Medical Sciences, University of New South Wales, Sydney, Australia. Department of Radiation Oncology and the Winship Cancer Institute, Emory University, Atlanta, Georgia. Departments of Biomedical Genetics and Pathology and Laboratory Medicine and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.
Funders
The Ovarian Cancer Research Foundation (OCRF), National Health and Medical Research Council of Australia
National Institute of Health (US), Queensland Emory Development, National Stem Cell Foundation of Australia
Donald and Joan Wilson Ovarian Cancer Research Foundation, Mater Foundation
Aim
It was previously shown that the G9a protein can also affect the activity of a second histone methyltransferase. Furthermore, G9a and EZH2 proteins are frequently over expressed in a variety of cancer types, suggesting that their activity may be required for both the initiation and progression of the disease. Moreover, overexpression of either enzyme correlates with poor survival outcome in patients with cancer ( EZH2). The research aims to investigate role of the G9a protein in tumour cell growth and uncover the precise mechanism for previous findings.
Terminology
EHMT2 (G9a) is a histone methyltransferase
Histone– A histone is a protein that provides structural support to a chromosome.
Histone methyltransferases– HMTs are a class of enzymes that mediate the methylation of lysine or arginine residues of histones.
IL24 protein – interleukin 24 is a protein in the interleukin family, a type of cytokine signaling molecule in the immune system. This interleukin is also known as melanoma differentiation-associated 7 (mda-7) due to its discovery as a tumour suppressing protein
Apoptosis– a form of programmed cell death that occurs in multicellular organisms
EZH2- The EZH2 gene provides instructions for making a type of enzyme called a histone methyltransferase
Upregulation – process of increasing the response to a stimulus
QPCR- stands for quantitative polymerase chain reaction and is a technology used for measuring DNA using PCR
Chromatin– a substance within a chromosome consisting of DNA and protein
Immunoprecipitation- technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins.
RNA– stands for ribonucleic acid, which is a long, single-stranded chain of cells that processes protein.
Method
A panel of human breast, ovarian, and melanoma cell lines were studied. RNA sequencing analysis was carried out at Emory University’s Yerkes NHP Genomics Core. Mapping and differential expression analysis was then performed in collaboration with the Medical Genomics Laboratory at QIMR Berghofer.
qPCR and chromatin immunoprecipitation histone methyltransferases were conducted. Comparison of gene expression between normal and tumor tissues were obtained from the GENT2 database.
Results
Compared to normal cells, ovarian cancer cells have a higher level of G9a protein. After drug therapy inhibiting the G9a function, cancer cells grow more slowly and can be killed completely. drug therapy inhibited specific proteins in model human tumour cells, allowing an increase in another protein, known as IL24, which kills the tumour cells. The anticancer effects of the dual inhibition of G9a and EZH2 are due to the derepression of specific set of genes that efficiently mimic the PDTstress phenotype in cancer cells.
Relevance
This research has identified a new drug therapy which can inhibit specific proteins (G9a and EZH2) in model cancer cells. This will allow the IL24 protein to stimulate tumour cell death. The authors’ propose that dual inhibition of G9a and EZH2 represents a novel strategy that can robustly induce cell death in multiple tumor types. If successful, this novel therapy could be used to treat multiple cancers, including ovarian cancer, breast cancer and melanoma.
HRA Comment
The average rate of successful translation from animal models to clinical cancer trials is less than 8% therefore human-relevant research is required to overcome species barriers. It is promising to see such research attract multiple funders and provide increased hope of increased survivability rates.