Aggressive cancer exploits MYC oncogene to amplify global gene activity
Whitehead Institute researchers have determined the mechanism used by c-Myc to increase the expression of all active genes in cancer cells. Elevated levels of c-Myc are linked to increased rates of metastasis, disease recurrence, and mortality in cancer patients. Guided by this new model, researchers hope to find ways to restrict c-Myc's activity to eradicate cancer cells that become dependent on c-Myc for their survival.
For a cancer patient, over-expression of the MYC oncogene is a bad omen.
Scientists have long known that in tumor cells, elevated levels of MYC's protein product, c-Myc, are associated with poor clinical outcomes, including increased rates of metastasis, recurrence, and mortality. Yet decades of research producing thousands of scientific papers on the subject have failed to consistently explain precisely how c-Myc exerts its effects across a broad range of cancer types. Until now, that is.
The prevailing theory emerging from this massive body of research has been that in tumor cells, c-Myc affects the expression of specific genes or sets of genes—that so-called Myc target genes are being selectively activated or repressed, leading to aberrant cellular behavior. Now, however, researchers in the lab of Whitehead Institute Member Richard Young are dispelling this commonly held notion, showing that elevated expression of c-Myc amplifies the activity of all expressed genes in tumor cells of multiple cancer types. It turns out that high levels of c-Myc send a tumor cell's gene expression program into overdrive. Transcription increases dramatically, allowing malignant cells to overwhelm factors that might normally hamper their growth and proliferation. This surprising finding, published in this week's issue of the journal Cell, provides a simple, elegant explanation for how a single protein can have such profound effect in so many and varied types of cancer. The newly revealed mechanism may also help scientists develop novel therapeutic approaches that disrupt c-Myc's activity.
"MYC is a key driver in most major cancers, but it has been notoriously difficult to drug," says Young, who is also a professor of biology at MIT. "Now that we know the mechanism by which c-Myc acts, we can go after the components of that mechanism as potential drug targets. This research creates an even stronger impetus to find a way to drug the thing."
One potential drawback to thwarting c-Myc's activity is the important role it plays in normal cell division. That role is so powerful that cells co-evolved an emergency death pathway to keep c-Myc expression in check. If c-Myc's production spins out of control in an otherwise normal cell, the cell immediately commits suicide through a process called apoptosis. But in cancer cells in which c-Myc is overproduced, this suicide pathway is compromised, allowing the cell to survive and proliferate.
"MYC is the most deregulated gene in cancer," says Charles Lin, a graduate student in the Young lab and co-author of the Cell paper. "It's been called a bad-boy, a Swiss army knife, and a jack-of-all-trades because, according to previous research, it could do everything under the sun in a cancer cell. But most of the different attributes ascribed to MYC are contradictory or seemingly incompatible."
Propelled by its earlier research that identified c-Myc as an important regulator of transcription in embryonic stem cells, the Young lab began to focus on c-Myc's activity within cancer cells. Lab members found that as the expression of c-Myc increases in these cells, the protein attaches to the promoters and enhancers of all active genes, thereby amplifying the active genes' transcription. The heightened transcription produces cells bloated with excessive RNAs and proteins capable of altering normal cellular functions. Researchers observed this phenomenon in cells from a host of cancers, including Burkitt's lymphoma, small cell lung cancer, multiple myeloma, and glioblastoma multiforme.
"The previous research now makes sense – finally!" says Jakob Lovén, co-author and postdoctoral researcher in the Young lab. "Our findings provide a way to unify everybody's seemingly conflicting data. I think that's really nice. Instead of saying 'you're all wrong,' we're saying 'you're all right, and here's why.' The model makes a lot of sense in terms of the biology that has been described so far."
With a better understanding of how c-Myc can wreak so much damage, the Young lab is turning its efforts to disrupting c-Myc's activity. Although cancer cells that overproduce c-Myc are associated with poor clinical outcomes, their reliance on c-Myc for survival may represent an Achilles' heel. When these "Myc-addicted" cells are deprived of c-Myc in vitro, even for a short period of time, they quickly die. Research in mice has shown that, Myc-addicted tumors deprived of the protein shrink dramatically. Despite c-Myc's necessary role in normal cell division, particularly in tissues with rapid cell turnover, such as the intestine and blood, these mouse studies have shown that if c-Myc activity is restored after a brief period, normal tissues quickly bounce back, while tumors are unable to regain their footing.
"So what we think now is that potentially, if drugs can tune down the levels of transcription just slightly, this might be catastrophic for the Myc-addicted cancer cells," says Peter Rahl, co-author and postdoctoral researcher in the Young lab. "You wouldn't need to abolish all transcription because that would be toxic to your other cells. So we're hoping that our model will show us ways to create a therapeutic window where the Myc-addicted cells just won't be able to adapt to lower levels of transcripts."
More information: "Transcriptional Amplification in Tumor Cells with Elevated c-Myc" Cell, September 28, 2012, in print.
Journal reference: Cell
Provided by Whitehead Institute for Biomedical Research
- Stopping ovarian cancer by blocking proteins coded by notorious gene Dec 15, 2008 | not rated yet | 0
- Lymphoma therapy could deliver a double punch Apr 30, 2012 | not rated yet | 0
- Scientists identify a critical tumor suppressor for cancer Aug 02, 2012 | not rated yet | 0
- Protein may represent a switch to turn off B cell lymphoma May 07, 2012 | not rated yet | 0
- Researchers uncover one force behind the MYC oncogene in many cancers Jul 28, 2009 | 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
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 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...
- More from Physics Forums - Medical Sciences
More news stories
In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used ...
Cancer 4 hours ago | not rated yet | 0
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ...
Cancer 4 hours ago | not rated yet | 0
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer 7 hours ago | 5 / 5 (1) | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer 8 hours ago | 5 / 5 (1) | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer 8 hours ago | 5 / 5 (3) | 0
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
8 hours ago | 5 / 5 (3) | 0 |
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
2 hours ago | 5 / 5 (1) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
5 hours ago | 5 / 5 (1) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
5 hours ago | 5 / 5 (2) | 0 |
(Medical Xpress)—Regulating the distribution of power in neurons is done by a system that makes the national electric grid look simple by comparison. Each neuron has several thousand mitochondria confined ...
23 hours ago | 4.9 / 5 (9) | 0 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
2 hours ago | not rated yet | 0