Introducing epigenetic changes to convert healthy tissue to cancerous

Introducing epigenetic changes to convert healthy tissue to cancerous

Changing the epigenetic code of a single gene is enough to cause a healthy breast cell to begin a chain reaction and become abnormal, according to research published in Nature Communications.

Epigenetic changes are a hallmark of cancer, but up until now, it has not been known whether these changes on their own are sufficient to push healthy cells down the cancer path.

Using a CRISPR-dCas9 epigenetic editing tool, the researchers methylated different genes in healthy breast cells and found that those changes were sufficient to cause the cells to undergo 'hyperproliferation' - abnormally rapid cell division which is an early stage of tumor initiation.

The research, using cells from the Breast Cancer also shows that the epigenetic changes are inherited as long as the cell divides, and that the team's manipulations permanently and negatively affected the biology of a normal breast cell from a healthy individual.

Authors show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2ARASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest.

The data show that the key driver of this phenotype is repression of CDKN2A transcript p16 where myoepithelial cells harbor cancer-like gene expression but do not exhibit anchorage-independent growth. 

Lead researcher said: "It's surprising that cells from several healthy individuals are so permissive to gaining this epigenetic change and that one 'hit' from an epigenetic editing tool is sufficient to set off this chain reaction of epigenetic inheritance and establish a cancer cell-like gene expression signature."

The findings may help scientists to better understand the earliest epigenetic changes which can initiate abnormal cell processes, and the transition between the pre-disease state and cancer. This could help with the development of new biomarkers for earlier diagnosis.

In the future, epigenetic editing could also be used to design novel therapies by initiating permanent changes to cell biology. This may be a more viable or alternative way forward for gene editing as any potential mistakes would be less damaging than directly editing the DNA sequence, and epigenetic editing would be more easily reversible if needed.

The author also explains that the findings could have an impact on our knowledge of ageing and cancer: "Epigenetic fluctuations happen all the time in our cells. We know that, during ageing, our epigenome is progressively distorted - so called 'epigenetic drift'. It will therefore be exciting to find out if this drift is responsible for initiating or accelerating ageing-associated diseases. Age is the biggest risk in cancer so our work highlights the importance of understanding the mechanism behind epigenetic drift."