Faulty Cell Cycle Brakes Linked To Breast Cancer

A protein that represses an important cell division checkpoint may have far reaching effects in cancer.

AsianScientist (Nov. 26, 2012) – When a cell proliferates out of control, it is usually because it loses control at a cell cycle checkpoint – the ‘fail-safe brakes’ of the cell.

One key checkpoint protein is p21, a cyclin-dependent kinase inhibitor (CKI) that gives the ‘all signals go’ for DNA synthesis to take place.

Dr. Sameer Phalke and colleagues at the A*STAR Institute of Molecular and Cell Biology (IMCB) recently discovered a protein that acts as an oncogene in breast cancer by repressing p21 expression, thereby promoting growth and preventing the senescence of breast cancer cells1.

The oncogenic protein, called protein arginine methyltransferase 6 (PRMT6), is a member of a family of enzymes that methylate proteins on arginine residues. PRMT enzymes function as transcriptional co-activators or co-repressors by binding to DNA and changing their expression status.

After their initial discovery that the expression of PRMT6 was elevated in clinical breast tumor samples, the researchers tested whether PRMT6 played a role in the growth of breast cancer cell lines.

Suppression of PRMT6 expression in breast cancer cells led to cell cycle arrest, cellular senescence, and reduced growth in soft agar assays. Similar experiments in severe combined immunodeficiency (SCID) mice resulted in slower growing tumors.

Delving further into the molecular mechanism, the team found that PRMT6 acts as a transcriptional co-repressor by binding to the promoter of the cdkn1a gene encoding for the p21 protein, directly preventing p21 from being synthesised.

p21 is normally tightly controlled by the tumour suppressor p53, which is mutated in nearly 50 percent of all cancers. Together these two proteins form an important axis in the cell cycle checkpoint system in response to DNA damage. Here, the effect of PRMT6 on p21 was independent of p53, which makes the findings of this study relevant to cancers irrespective of their p53 status.

The data may open up the possibility of finding more targeted therapies – such as a PRMT6-specific inhibitor – for the treatment of breast cancer, said Phalke.

“It would be very useful to find new inhibitors to specifically target PRMT6 activity, since the currently available compounds are targeting the entire PRMT family of enzymes,” he said.

His next step is to find other targets of PRMT6 and its possible co-factors, and to investigate whether PRMT6 is over-expressed in other cancers such as lung and ovarian cancers.

The article can be found at: Phalke S et al. (2012) p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6.

——

Copyright: Asian Scientist Magazine; Photo: MrDays/Flickr/CC.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

David Tan is a post-doctoral researcher at the A*STAR Institute of Medical Biology, Singapore. David received a PhD in stem cell biology from the University of Cambridge, UK.

Related Stories from Asian Scientist