Reversing therapy resistance in cancer - determining the role of epigenetic modifying enzymes

Our approach is to reverse the changes that have occurred in tumour cells when they develop resistance to the front line drugs. The genetic makeup of cells is a significant contributor to cancer, but it is not the only component that gives rise to the disease. Changes in DNA methylation patterns and/or post-translational modifications of histones (collectively known as epigenetic modifications) are a mechanism for regulation of gene expression in response to physiological changes in the body. There is now strong evidence that epigenetic alterations are key drivers of cancer progression. Epigenetic modifiers are commonly overexpressed in many cancer types. We have shown previously that inhibitors of these enzymes are potent suppressors of tumour growth either alone or in combination with other therapeutic drugs. Therefore, the proposed study is to examine the mechanism by which these epigenetic inhibitors reverse resistance to standard therapies.
Aim
To determine the role of epigenetic modifying enzymes in cancer therapy resistance by integrating epigenetic, genomic, trancriptomic and proteomic data.
Approaches
1. Cellular models and treatments
2. Characterisation of the lysine methyltransferases and demethylases
3. Promoter methylation analysis
4. Protein complex purification and proteomics
5. Immunoprecipitation assays
6. In vivo mouse models

References
1. Casciello et al., “G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis” Proc Natl Acad Sci U S A. 114(27):7077-7082 2017.
2. Lee et. al., EZH2-Generates a Methyl Degron that is Recognized by the DCAF1/DDB1/ CUL4 E3 Ubiquitin Ligase Complex. Molecular Cell, 48, 572–586, 2012.
3. Lee et. al., Negative Regulation of Hypoxia Response by Induced Reptin Methylation. Molecular Cell. 39, 71-85, 2010.

For more information on this research group: http://www.qimrberghofer.edu.au/lab/epigenetics-disease-group/