Cancer study overturns current thinking about gene activation
(Medical Xpress)—A new Australian study led by Professor Susan Clark from Sydney's Garvan Institute of Medical Research shows that large regions of the genome – amounting to roughly 2% – are epigenetically activated in prostate cancer.
Regions activated contain many prostate cancer-specific genes, including PSA (prostate specific antigen) and PCA3, the most common prostate cancer markers. Until now, these genes were not known to be regulated epigenetically.
A previous study from Professor Clark's lab showed that similarly large regions of the prostate cancer genome are also epigenetically silenced, demonstrating a structured rearrangement of the cancer epigenome.
Epigenetics looks at biochemical changes that affect how the genome is organised in the cell nucleus, which in turn controls how genes are expressed. Attachment or detachment of certain molecules can literally open or close DNA's structure, allowing a gene to be expressed if the structure is opened, and silenced if the structure is closed.
Among other aspects of epigenetic activation, the new study shows that the epigenetic process known as 'methylation' can activate genes, often by changing the gene start site, overturning the prevailing dogma that DNA methylation can only silence genes.
The findings as a whole have extensive ramifications for cancer diagnosis and treatment, including epigenetic-based gene therapies, as they require the targeting of domains of genes, as opposed to single genes.
PhD student Saul Bert and Professor Clark used gene expression profiling data and genome-wide sequencing technology from prostate tumour cells to determine which parts of the genome were epigenetically activated in prostate cancer. They then examined the mechanisms behind activation, publishing their findings in the very prestigious international journal Cancer Cell, now online.
DNA is made up of building blocks of nucleic acid known as 'base pairs', specifically guanine-cytosine (GC) and adenine-thymine (AT). Unlike other parts of the genome, there are dense clusters of CG pairs very close to gene start sites. These CG clusters, known as 'CpG islands', are where methylation occurs.
"When I started my PhD, we were looking to see if there was loss of methylation at CpG islands, causing gene activation in cancer," said Saul Bert.
"We took a whole genome approach, looking at all the gene transcription start sites that included CpG islands. What we saw surprised us, because we saw gene activation at hypermethylated sites – that went against current thinking.
"We went on to show in the lab that if you methylate CpG islands that are very close to transcription start sites, but not exactly on top of them, then it's possible to turn genes on.
"While the realisation that methylation can trigger gene activation represents a paradigm shift in thinking, our other finding - that the prostate cancer genome contains domains that harbour multiple gene families, tumour related genes, microRNAs and cancer biomarkers – is equally important. These domains are simultaneously switched on through significant epigenetic remodelling.
"In this study, we identified 35 domains including 251 genes. While the genes may seem to be functionally unrelated, their coordinated regulation in the cancer genome suggests the presence of epigenetic 'master controllers' that can switch on or off very large regions of DNA."
Project leader Professor Clark believes the study will have a significant impact on our understanding of diagnostic tests and on chemotherapy treatment.
"What we are seeing in prostate cancer would apply to other cancers. The big new finding is about the ways in which neighbouring genes are being co-ordinately activated in cancer," said Professor Clark.
"The increased expression is not just due to genetic amplification – but we now show is also due to unraveling of the cancer genome.
"We need to understand this process more deeply to determine the impact of current epigenetic therapies that are aimed at promoting gene activation rather than suppressing oncogene expression."
Provided by Garvan Institute of Medical Research
- What it might take to unravel the 'lean mean machine' that is cancer Feb 23, 2010 | not rated yet | 0
- Gene switch sites found mainly on 'shores,' not just 'islands' of the human genome Jan 18, 2009 | not rated yet | 0
- Researchers discover biomarkers for prostate cancer detection, recurrence May 14, 2012 | not rated yet | 0
- Ovarian cancer advances when genes are silenced Dec 13, 2010 | not rated yet | 0
- Epigenetic causes of prostate cancer Sep 05, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be villous adenoma in colon, if there are no villi there
17 hours ago As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
- More from Physics Forums - Medical Sciences
More news stories
(HealthDay)—The American Cancer Society, which is celebrating on Wednesday a century of fighting a disease once viewed as a death sentence, is making a pledge to put itself out of business.
Cancer 7 hours ago | not rated yet | 0
National Lung Screening Trial (NLST) investigators also conclude that the 20 percent reduction in lung cancer mortality with low-dose computed tomography (LDCT) versus chest X-ray (CXR) screening previously reported in the ...
Cancer 7 hours ago | not rated yet | 0
Researchers have developed a new drug delivery system that allows inhalation of chemotherapeutic drugs to help treat lung cancer, and in laboratory and animal tests it appears to reduce the systemic damage ...
Cancer 11 hours ago | not rated yet | 0 |
When turned on, the gene p53 turns off cancer. However, when existing drugs boost p53, only a few tumors die – the rest resist the challenge. A study published in the journal Cell Reports shows how: tumors that live even i ...
Cancer 11 hours ago | not rated yet | 0 |
Study leader, Professor John Mathews from the University of Melbourne said this small increase in cancer risk must be weighed against the undoubted benefits from CT scans in diagnosing and monitoring disease.
Cancer 15 hours ago | not rated yet | 0
Existing research shows that bicyclists who wear helmets have an 88 percent lower risk of brain injury, but researchers at Boston Children's Hospital found that simply having bicycle helmet laws in place showed a 20 percent ...
50 minutes ago | not rated yet | 0
Swiss scientists reveal the mechanism responsible for aging hidden deep within mitochondria—and dramatically slow it down in worms by administering antibiotics to the young.
11 hours ago | 4.9 / 5 (7) | 0 |
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
11 hours ago | 4 / 5 (1) | 0 |
Until now, little was scientifically known about the human potential to cultivate compassion—the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.
8 hours ago | 5 / 5 (2) | 2 |
(HealthDay)—Migraines and depression can each cause a great deal of suffering, but new research indicates the combination of the two may be linked to something else entirely—a smaller brain.
8 hours ago | 4 / 5 (2) | 0 |
A new approach for immunizing against influenza elicited a more potent immune response and broader protection than the currently licensed seasonal influenza vaccines when tested in mice and ferrets. The vaccine ...
9 hours ago | not rated yet | 0 |