The development of tumours coincides with the activation of several cancer genes as well as the inactivation of other tumour-suppressing genes owing to damage to the DNA and to the fact that the cancer cells manage to switch off the transcription of tumour-suppressor genes. To identify what might be regulating this silencing, the researchers studied PTEN, one of the most commonly inactivated tumour-suppressor genes. It has long been believed that the switching-off process is irreversible, but the team has now shown that silenced PTEN genes in tumour cells can be ‘rescued’ and re-activated by a ‘pseudogene’, a type of gene that, unlike normal genes, does not encode an entire protein.
“We identified a new non-protein encoding pseudogene, which determines whether the expression of PTEN is to be switched on or off,” says research team member Per Johnsson, doctoral student at Karolinska Institutet’s Department of Oncology-Pathology. “What makes this case spectacular is that the gene only produces RNA, the protein’s template. It is this RNA that, through a sequence of mechanisms, regulates PTEN. Pseudogenes have been known about for many years, but it was thought that they were only junk material.”
No less than 98 per cent of human DNA consists of non-protein encoding genes (i.e. pseudogenes), and by studying these formerly neglected genes the researchers have begun to understand that they are very important and can have an effect without encoding proteins. Using model systems, the team has shown that the new pseudogene can control the expression of PTEN and make tumours more responsive to conventional chemotherapy.
“This means that we might one day be able to re-programme cancer cells to proliferate less, become more normal, and that resistance to chemotherapy can hopefully be avoided,” says Per Johnsson. “We also believe that our findings can be very important for the future development of cancer drugs. What we’re seeing here is just the tip of the iceberg. The human genome conceals no less than 15,000 or so pseudogenes, and it’s not unreasonable to think that many of them are relevant to diseases such as cancer.”
The study was conducted in collaboration with scientists at The Scripps Research Institute, USA, and the University of New South Wales, Australia, and was made possible with grants from the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Cancer Research Funds of Radiumhemmet, Karolinska Institutet’s KID programme for doctoral studies, the Swedish Research Council, the Erik and Edith Fernström Foundation for Medical Research, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute and the National Institutes of Health.
Publication: ‘A pseudogene long noncoding RNA network regulates PTEN transcription and translation in human cells’, Per Johnsson, Amanda Ackley, Linda Vidarsdottir, Weng-Onn Lui, Martin Corcoran, Dan Grandér och Kevin V. Morris, Nature Structural and Molecular Biology, AOP 24 February 2013, doi: 10.1038/nsmb.2516.
Caption: Per Johnsson