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DNA repair defect reveals bladder cancer weakness

The genetic material – your DNA – contained within the nucleus of cells holds the 20,000 genes that make up the human genome. Each gene is a code that can be transcribed into a long chain of protein building blocks called amino acids. The order of these amino acids defines the chains chemistry, which, in turn, is primarily responsible for how the chain naturally “folds” or arranges itself into the more complex structures we know as proteins. We can think of proteins as “effector” molecules - the ones capable of causing things to happen in a cell, such as producing energy for growth or cell division.

How much and when specific genes are “activated” or “switched on” to produce proteins is controlled by many processes – some we know a lot about and others we know very little - and occurs in response to a wide range of stimuli. One of the processes that switches genes on or off (known as gene expression) is called DNA methylation – a core process studied in the field of research called epigenetics.

Dr Apostolos Klinakis is a researcher based at the Biomedical Research Foundation of the Academy of Athens, Greece, who has spent his career studying the function of proteins, including several implicated in the development of cancer. Since 2016, his team have been working on a Worldwide Cancer Research project trying to pinpoint proteins that drive bladder cancer.

“We recently discovered that in cancer cells from a variety of different tumour types, there is a gene called KMTC2 that is downregulated, meaning that it is not ‘switched on’ or ‘expressed’ as much as you would expect in a healthy cell. This gene seems to be highly downregulated in bladder cancer so we wanted to study the effect of this gene in relation to cancer to understand how it could be used as a therapeutic target,” said Dr Klinakis.

The code within the KMTC2 gene results in the building of a type of protein known as a histone methyltransferase. This protein sticks to certain regions of DNA and influences how and when genes near those regions are activated through the process of DNA methylation. As expected, when Dr Klinakis’ team blocked the KMTC2 gene, they found that it affected expression of many other genes. The team were particularly interested to learn that some of these genes were ones involved in the repair of damaged DNA.

“Our research shows that low expression of KMT2C in cancer cells leads to an abnormal response to DNA damage and deficiencies in the molecular machinery used by cells to repair DNA. Interestingly, this means that these cancer cells are sensitized to a class of drug called PARP inhibitors, opening a window for therapeutic intervention in not only bladder cancer, but a range of tumours including lung, head & neck, and colorectal carcinoma,” explained Dr Klinakis.

PARP inhibitors, such as the drug olaparib, work by targeting defects in the ability of cancer cells to repair damage to DNA. Olaparib is already used to treat some ovarian and breast cancers, but evidence is emerging that drugs in this class could be used to treat a wide range of cancers.

“At the research level, we expect that our study will encourage further experimentation on the role of epigenetic regulators like KMTC2 in the cells response to DNA damage and DNA repair. At the clinical level, we hope that it will encourage studies for validation of our findings in the clinic and perhaps lead to testing of PARP inhibitors in bladder cancer patients as well.”

Bladder cancer is the sixth most common cancer worldwide and affects nearly 550,000 people each year. In the UK, over 10,000 people are diagnosed with bladder cancer each year, and half of them will die from the disease within 10 years of their diagnosis. Research like Dr Klinakis’ is vital to find new and more effective ways to treat bladder cancer, and his team’s promising discovery shows that a drug already saving the lives of some cancer patients, could one day be used to treat many more people.

Dr Klinakis’ research was recently published in EMBO Press.

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