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Research sheds light on the progression of cancer

September 14, 2016

The progression of cancer has remained one of the biggest mysteries in cancer biology. When a normal cell turns cancerous, its 3 billion DNA base pairs undergo a massive ‘epigenetic’ shift – a series of large-scale changes called methylation. These changes often switch off key anticancer genes that contribute to cancer progression.

Researchers at the Garvan Institute of Medical Research have discovered how DNA becomes methylated at key sites across the genome in cancer cells, leading to gene inactivation. The study also shows that the protein MBD2, which binds to methylated DNA sequences, also plays a wide-ranging role in guiding the process of DNA methylation.

Study co-leaders, Professor Susan Clark and Dr Clare Stirzaker, are experts in the cancer-associated methylation of ‘CpG islands’. These are regions of DNA that sit near many genes and help control their activity.

In an effort to understand how the pattern of DNA methylation changes in cancer, the researchers conducted a detailed investigation into how CpG islands go from an unmethylated state to a heavily methylated one.

CpG islands and methylation in cancer

“What we see in normal cells is that the DNA within CpG islands has very low levels of methylation. In fact, you can think of these regions as islands in a sea of methylation, because the rest of the genome in a normal cell has quite high DNA methylation levels,” said Professor Clark.

“This low level of methylation of CpG islands is important, because it means the genes that the islands control stay active. These include tumour suppressor genes, which are named because they carry out important cancer-avoiding tasks – keeping cell division under control, for instance, and repairing any mistakes introduced into the DNA sequence.”

But in cancer, the landscape of DNA methylation changes – which has major impacts on cell function.

“The DNA methylation landscape in a cancer cell is entirely different to that in a normal cell,” Professor Clark said.

“A remarkable switch occurs at CpG islands – which become highly methylated in cancer, effectively silencing a host of genes including tumour suppressor genes.”

“Notably, the opposite is true for the remainder of the genome in a cancer cell. As CpG islands become more methylated in cancer, the DNA in the surrounding ‘sea of methylation’ loses its associated methyl groups.”

Where does methylation start?

Dr Stirzaker said that in a previous study, the research team showed that changes begin with ‘seeding’ methylation, in which a few scattered sites within the CpG island become methylated first, paving the way for the spread of methylation across the island.

In the new study, the researchers uncovered an unexpected understanding of how DNA methylation at CpG islands progresses beyond those initial ‘seeds’.

“We’ve been looking, in particular, at the role of a methyl-binding protein called MBD2,” said Dr Stirzaker.

“In the past, MBD2 and the other proteins in the same family were well studied by our group and others, and they were thought to be just ‘readers’ of DNA methylation across the genome, because they recognised methylation sites and bound to them.”

“Now, we have found that MBD2 is so much more than a ‘reader’ of methylation – it is a ‘writer’ of methylation as well. That is, MBD2 is actively involved in reshaping the landscape of methylation across the genome.”

MBD2 and the progression of prostate cancer

The researchers looked first at how DNA methylation at one particular CpG island in prostate cancer cells is affected when MBD2 is absent. They then extended their studies, taking a genome-wide approach by looking at hundreds of thousands of DNA methylation sites in the same cells.

Finally, the researchers compared methylation information from the prostate cancer cell line with clinical samples of prostate cancer that they retrieved from The Cancer Genome Atlas (TCGA).

They showed that the affected CpG islands and shores are likely to be important in cancer.

“We found that the regions in the cancer cell line that need MBD2 to trigger methylation at CpG islands are, to a large extent, the same regions that are heavily methylated in samples from prostate cancers.”

“That suggests that the ‘writing’ of methylation by MBD2 is likely to be relevant to the clinical progression of cancer,” Dr Stirzaker said.

The research was recently published in the online journal Oncogene. The news was first posted on Garvan’s website. Image of Professor Clark and Dr Stirzaker courtesy of Garvan.

The Australian Cancer Research Foundation has supported cancer research at Garvan by providing three grants, totalling AUD $6.13million, towards cutting edge cancer research equipment and technology.

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