Navigation Links
'Oncometabolite' linked with widespread alterations in gene expression
Date:1/18/2011

A new study finds that a metabolite commonly elevated in brain cancer and leukemia may promote tumorigenesis by altering the expression of a large number of genes. New research, published by Cell Press in the January 18th issue of the journal Cancer Cell, enhances the understanding of the link between metabolic deregulation and cancer and may help to guide development of new targeted cancer therapies.

More than 75% of low grade gliomas and secondary glioblastoma multiforme (GBM), and about 20% of acute myeloid leukemia (AML), exhibit mutations in genes for isocitrate dehydrogenase (IDH1 and IDH2). The tumor-derived mutations in IDH1 and IDH2 lead to loss of normal production of α-ketoglutarate (α-KG), which is required for over 60 enzymes known as dioxygenases, and a gain in the production of 2-hydroxygulatrate (2-HG), which is found at very low levels in normal cells.

"Although 2-HG has been proposed to be an 'oncometabolite', its mechanism of action is not known," explains senior study author, Dr. Yue Xiong from the University of North Carolina at Chapel Hill. "Previous work demonstrated that 2-HG and α-KG are structurally similar, suggesting that 2-HG might interfere with the ability of α-KG to bind to and activate dioxygenases." Dr. Xiong, co-authors Dr. Kun-Liang Guan from the University of California at San Diego and Dr. Shi-min Zhao from Fudan University in Shanghai, and their colleagues designed a series of experiments to uncover how 2-HG contributes to cancer and determine the functional relationship between α-KG reduction and 2-HG elevation.

The researchers discovered that 2-HG functioned as a competitive inhibitor of multiple α-KG-dependent dioxygenases. Some of these dioxygenases regulate methylation of histones, a group of proteins that contribute to the structural organization of chromatin, and methylation of DNA. Alteration of histone and DNA methylation is likely to have a substantial impact on regulation of gene expression and, quite possibly, promote tumor growth. The researchers also showed that a cell-permeable derivative of α-KG reversed the effects of 2-HG inhibition.

"Our findings support the notion that although D-2-HG may not play a significant role in the regulation of α-KG-dependent dioxygenases in normal cells because of its low level, it could play an important role under pathological conditions in tumor cells expressing mutated IDH1 or IDH2", concludes Dr. Xiong. "We also suggest that drugs mimicking α-KG merit exploration as a therapy for tumors that harbor an IDH1 or IDH2 mutation, either alone or in combination with inhibitors to reduce the 2-HG production."


'/>"/>

Contact: Elisabeth Lyons
elyons@cell.com
617-386-2121
Cell Press
Source:Eurekalert

Related medicine news :

1. High birth weight in First Nations babies linked to a higher risk of postneonatal death
2. Too Much TV May Be Linked to Heart Attack, Death Risk
3. High dietary fat, cholesterol linked to increased risk of breast cancer
4. Secondhand television exposure linked to eating disorders
5. Violence against mothers linked to 1.8 million female infant and child deaths in India
6. Tooth Loss May Be Linked to Memory Loss
7. Vitamins C and E linked to metabolic syndrome in low-income Ecuadorians
8. Infant hydrocephalus, seasonal and linked to farm animals in Uganda
9. Risk for alcoholism linked to risk for obesity
10. Chronic Nasal Congestion May Be Linked to Severe Asthma
11. Size of Key Brain Region Linked to Size of Your Social Network
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/24/2016)... (PRWEB) , ... June 24, 2016 , ... Those who ... with these feelings, many turn to unhealthy avenues, such as drug or alcohol abuse, ... Marne, Michigan, has released tools for healthy coping following a traumatic event. , Trauma ...
(Date:6/24/2016)... ... June 24, 2016 , ... The Pulmonary Hypertension Association (PHA) ... will receive two significant new grants to support its work to advance research ... anniversary by recognizing patients, medical professionals and scientists for their work in fighting ...
(Date:6/24/2016)... ... June 24, 2016 , ... Comfort Keepers® of San Diego, CA is ... Road To Recovery® program to drive cancer patients to and from their cancer treatments. ... the highest quality of life and ongoing independence. Getting to and from medical ...
(Date:6/24/2016)... Georgia (PRWEB) , ... June 24, 2016 , ... ... awards today at the Clinical Decision Making in Emergency Medicine conference in Ponte ... have authored journal articles published in Emergency Medicine Practice and Pediatric ...
(Date:6/24/2016)... ... June 24, 2016 , ... Strategic ... Frederick area economy by obtaining investment capital for emerging technology companies. SCP ... that have already resulted in more than a million dollars of capital investment ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... ITASCA, Ill. , June 23, 2016  In a startling ... states are failing their residents by lacking a comprehensive, proven plan ... , a definitive ranking of how states are tackling the ... rating to only four states – Kentucky , ... and Vermont . Of the 28 failing states, ...
(Date:6/23/2016)... Pa. , June 23, 2016 Bracket ... will launch its next generation clinical outcomes platform, Bracket eCOA ... Meeting held on June 26 – 30, 2016 in ... the first electronic Clinical Outcome Assessment product of its kind ... Booth #715. Bracket eCOA 6.0 is a flexible ...
(Date:6/23/2016)... , June 23, 2016  Guerbet announced today that ... Supplier Horizon Award . One of ... was recognized for its support of Premier members through ... clinical excellence, and commitment to lower costs. ... this recognition of our outstanding customer service from Premier," ...
Breaking Medicine Technology: