Antiviral enzyme can fuel the evolution of cancer

Breaking new ground 27. jul 2021 2 min Professor Charles Swanton Written by Kristian Sjøgren

An enzyme that cells normally use to combat viruses can be activated by cancer and result in incomplete replication of DNA and the development of cancer. Researchers view the enzyme as a possible target to combat cancer.

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In the past 5 years, researchers have investigated a special phenomenon in the development of cancer: that cancer often seems to use one of the body’s own enzymes to drive tumour growth.

The enzyme, APOBEC3, is part of the body’s natural defences against viral infections, including most notably HIV, but cancer can take over the activity of the enzyme and use it to speed up cell division, boosting the development of cancer and driving tumour growth.

Now an international team of researchers from Denmark and the United Kingdom has studied APOBEC3 in more detail, and a new study now shows that the cancer can take control of the enzyme in pre-invasive disease and use it to promote its own evolution.

The discovery therefore indicates that APOBEC3 may be a potential target for arresting the development of cancer at an early stage.

“Our study indicates that APOBEC3 is an enzyme that can be targeted with anticancer therapy and may be a good target for early treatment to limit evolution and resistance to therapy. Examining tumours following treatment may also be a target for treatment to prevent relapse,” explains Charles Swanton, Professor, Francis Crick Institute, London, United Kingdom.

The research has been published in Cancer Discovery.

Increased APOBEC3 in early-onset cancer

The researchers analysed messenger RNA (mRNA) and APOBEC protein from the tumours of people with different stages of pre-invasive breast and lung cancer. mRNA is the link between genes and proteins and a good indicator of the presence of a specific protein in a biological sample.

The researchers analysed the presence of APOBEC3 mRNA and protein and determined when APOBEC3 was most active in cancer evolution.

This showed that the cancer causes the cells to express APOBEC3 at the pre-invasive stage.

Closer examination of the activity showed that the expression of APOBEC3 appears to exacerbate DNA replication stress and chromosomal instability at the same time that the cancer cells initially stop dividing as they reach senescence.

All cells can divide a specific number of times until they reach senescence, but cancer cells always find ways to bypass this mechanism, and this is correlated with high expression of APOBEC3.

“Our studies show that the expression of APOBEC3 is triggered synchronously with senescence, induced by cancer-related DNA replication stress. We find that APOBEC3 itself drives further replication stress and chromosomal rearrangements. This means that considerable variation arises between the cancer cells at this early stage in the evolution of cancer,” says Charles Swanton.

Increased activity of APOBEC3 associated with chromosomal instability

The researchers examined the effects of the upregulation of APOBEC3 genes and found that APOBEC3 changes the rate at which DNA is copied.

The more rapidly DNA is copied, the greater the risk of error, leading to the incomplete replication of genomic DNA and chromosomal instability, which fuel mutations and diversity in the genetic material of cancer cells – exactly what cancer needs to continue its evolution.

“Natural selection and the ability to adapt to the environment require mutations and diversity, and the cancer cells overexpress APOBEC3 to achieve what they need to be able to adapt to the environment. This is one of the most prominent features of cancer cells, and the process begins at the early onset of cancer evolution with the activation of APOBEC3, which is otherwise part of the body’s antiviral defence mechanism,” explains Charles Swanton.

Potential new target to combat cancer

Charles Swanton believes the discovery has the potential to chart a new path for anticancer therapy.

If doctors can identify increased activity of APOBEC3 at an early stage, they can detect that the cancer is gathering strength to progress to the next stage of evolution.

Similarly, therapy targeting APOBEC3 may also represent a whole new angle for treating cancer.

However, this requires more research.

“APOBEC3 is a potentially new target for cancer therapy, but currently inhibiting it is very difficult. This is therefore a goal for future research,” says Charles Swanton.

Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution” has been published in Cancer Discovery. In 2020, the Novo Nordisk Foundation awarded a grant to co-author Jiri Bartek for the project Replication Stress: Mechanisms and Roles in Human Health and Disease.

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