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Written by xiao xia Edited by Wang Duoyu | Metformin (Metformin) can lower blood sugar by inhibiting the production of glucose in the liver.
It is the first-line drug for the treatment of type 2 diabetes and one of the most commonly prescribed drugs in the world.
Hundreds of millions of people are taking metformin
.
As an old drug, people's research on metformin has never stopped, and the research enthusiasm is also increasing.
Metformin always refreshes our understanding of it, and continues to bring people one surprise after another
.
In recent years, many studies have shown that in addition to lowering blood sugar, metformin also has the effect of weight loss
.
Many pre-clinical and clinical studies have also observed that metformin has beneficial effects in anti-aging, treatment of cognitive impairment, cancer, and cardiovascular diseases.
Therefore, metformin is also known as the "magic drug"
.
Ependymoma is a common brain tumor in the brain of children.
It usually occurs in the posterior cranial fossa.
Among them, PFA subtype has the highest incidence and malignancy.
It mainly occurs in children with an average age of 3 years, about 40% There is no cure
.
Therefore, finding effective targeted therapeutic drugs has become an urgent problem to be solved in the treatment of this tumor
.
Most cancers are caused by genetic mutations or errors, but the PFA subtype lacks such oncogene mutations.
It is mainly driven by epigenetics and is characterized by the inhibitory histone marker H3K27me3 (histone H3 lysine 27 Trimethylation) overall reduction and overexpression of EZHIP protein
.
PFA and midline glioma have many epigenetic similarities, and their appearance and age of onset are also very similar
.
Previous studies have found that key mutations in midline gliomas can alter cell metabolism, but it is not yet known whether the EZHIP protein overexpressed in PFA has the same effect
.
On October 6, 2021, researchers from the University of Michigan published a research paper titled: Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas in the journal Science Translational Medicine
.
The study revealed abnormal epigenetic changes in type A posterior fossa ependymal tumors (PFA), as well as active sugar metabolism and tricarboxylic acid cycle
.
The use of the diabetes drug metformin, which inhibits glucose metabolism, can reduce the protein EZHIP that causes abnormal epigenetic changes, thereby reducing the metabolic activity of tumor cells and inhibiting tumor growth
.
Therefore, metformin is expected to treat this rare childhood brain tumor
.
In order to determine the metabolic pathways up-regulated in PFA ependymoma, the research team used a multi-platform, unbiased method to evaluate gene expression and metabolomics in tumor tissues and patient-derived cell lines
.
They identified 53 genes upregulated by PFA ependymoma relative to PFB ependymoma from three independent, non-overlapping public data sets.
These genes are mainly related to glycolysis, tricarboxylic acid cycle, glutamate and phosphoric acid.
The pentose pathway (PPP) metabolism is involved
.
Next, the research team performed in vivo noninvasive magnetic resonance imaging (MRS) on 15 children with ependymoma, and used blind and retrospective methods to determine the concentration of metabolites in the body
.
They found that compared with PFB ependymoma, PFA ependymoma contains a higher concentration of citric acid and glutamic acid, and compared with ST ependymoma, PFA ependymoma contains a higher concentration of inositol , Taurine and creatine
.
These data indicate that PFA ependymoma has unique MRS imaging characteristics
.
The H3K27M mutation enhances glycolysis and tricarboxylic acid cycle metabolism through epigenetic activation of key metabolic genes
.
Because H3K27M and EZHIP exhibit epigenetic similarities, the research team wanted to determine whether EZHIP can upregulate these pathways in a similar manner
.
The results showed that, compared with PFB, the expression of EZHIP in PFA was increased, which corresponds to the overall decrease in H3K27me3 and the increase in H3K27ac
.
In PFA, elevated EZHIP concentration is associated with low progression-free survival and low overall survival
.
Compared with tumors related to the bottom of the fourth ventricle, EZHIP and H3K27ac were higher in tumors related to the top and lateral crypts
.
These data indicate that high EZHIP protein abundance is associated with poor prognosis of PFA
.
In addition, PF ependymoma with high expression of H3K27ac and EZHIP is related to the tumor location of the top and lateral crypts of the fourth ventricle
.
According to the chip sequence analysis, the research team noticed that a key component of the AMP-activated protein kinase (AMPK) complex is closely related to the expression of EZHIP and H3K27ac
.
AMPK is a key metabolic sensor that can be activated by metformin
.
Because metformin can also inhibit the citric acid cycle, the research team concluded that metformin treatment can reduce the citric acid cycle metabolites in PFA cells
.
In addition, metformin has shown strong anti-cancer effects and is currently being tested in more than 250 cancer clinical trials
.
So the research team evaluated the sensitivity of the PFA cell line to metformin
.
The results showed that the PFA cell line was sensitive to high-dose metformin treatment, and down-regulated proteins related to glycolysis, tricarboxylic acid cycle, pyruvate metabolism, and PPP
.
In addition, metformin reduces tumor growth and EZHIP in the body, and increases H3K27me3
.
These results indicate that metformin inhibits PFA's tricarboxylic acid cycle and pentose phosphate pathway (PPP) metabolism, and down-regulates EZHIP to increase total H3K27me3, achieving the effect of inhibiting tumor growth
.
In general, this work clarified the metabolic characteristics of type A posterior fossa ependymoma (PFA), and the initiator of this metabolic characteristic-EZHIP protein
.
The drug metformin, which inhibits the glycometabolism pathway, has a significant effect, which can shrink tumors and prolong survival.
The mechanism is to inhibit EZHIP and slow down the sugar metabolism of tumors
.
This study gave people a good idea that not all tumors are caused by DNA mutations.
Posterior fossa ependymomas like this are driven by epigenetic changes, which increase tumor metabolic activity.
, The use of antimetabolites must not only directly reduce tumor metabolism, but also directly or indirectly target epigenetic materials to achieve the fundamental cure of the disease
.
Link to the paper: https:// is open for reprinting, welcome to forward to Moments and WeChat groups
It is the first-line drug for the treatment of type 2 diabetes and one of the most commonly prescribed drugs in the world.
Hundreds of millions of people are taking metformin
.
As an old drug, people's research on metformin has never stopped, and the research enthusiasm is also increasing.
Metformin always refreshes our understanding of it, and continues to bring people one surprise after another
.
In recent years, many studies have shown that in addition to lowering blood sugar, metformin also has the effect of weight loss
.
Many pre-clinical and clinical studies have also observed that metformin has beneficial effects in anti-aging, treatment of cognitive impairment, cancer, and cardiovascular diseases.
Therefore, metformin is also known as the "magic drug"
.
Ependymoma is a common brain tumor in the brain of children.
It usually occurs in the posterior cranial fossa.
Among them, PFA subtype has the highest incidence and malignancy.
It mainly occurs in children with an average age of 3 years, about 40% There is no cure
.
Therefore, finding effective targeted therapeutic drugs has become an urgent problem to be solved in the treatment of this tumor
.
Most cancers are caused by genetic mutations or errors, but the PFA subtype lacks such oncogene mutations.
It is mainly driven by epigenetics and is characterized by the inhibitory histone marker H3K27me3 (histone H3 lysine 27 Trimethylation) overall reduction and overexpression of EZHIP protein
.
PFA and midline glioma have many epigenetic similarities, and their appearance and age of onset are also very similar
.
Previous studies have found that key mutations in midline gliomas can alter cell metabolism, but it is not yet known whether the EZHIP protein overexpressed in PFA has the same effect
.
On October 6, 2021, researchers from the University of Michigan published a research paper titled: Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas in the journal Science Translational Medicine
.
The study revealed abnormal epigenetic changes in type A posterior fossa ependymal tumors (PFA), as well as active sugar metabolism and tricarboxylic acid cycle
.
The use of the diabetes drug metformin, which inhibits glucose metabolism, can reduce the protein EZHIP that causes abnormal epigenetic changes, thereby reducing the metabolic activity of tumor cells and inhibiting tumor growth
.
Therefore, metformin is expected to treat this rare childhood brain tumor
.
In order to determine the metabolic pathways up-regulated in PFA ependymoma, the research team used a multi-platform, unbiased method to evaluate gene expression and metabolomics in tumor tissues and patient-derived cell lines
.
They identified 53 genes upregulated by PFA ependymoma relative to PFB ependymoma from three independent, non-overlapping public data sets.
These genes are mainly related to glycolysis, tricarboxylic acid cycle, glutamate and phosphoric acid.
The pentose pathway (PPP) metabolism is involved
.
Next, the research team performed in vivo noninvasive magnetic resonance imaging (MRS) on 15 children with ependymoma, and used blind and retrospective methods to determine the concentration of metabolites in the body
.
They found that compared with PFB ependymoma, PFA ependymoma contains a higher concentration of citric acid and glutamic acid, and compared with ST ependymoma, PFA ependymoma contains a higher concentration of inositol , Taurine and creatine
.
These data indicate that PFA ependymoma has unique MRS imaging characteristics
.
The H3K27M mutation enhances glycolysis and tricarboxylic acid cycle metabolism through epigenetic activation of key metabolic genes
.
Because H3K27M and EZHIP exhibit epigenetic similarities, the research team wanted to determine whether EZHIP can upregulate these pathways in a similar manner
.
The results showed that, compared with PFB, the expression of EZHIP in PFA was increased, which corresponds to the overall decrease in H3K27me3 and the increase in H3K27ac
.
In PFA, elevated EZHIP concentration is associated with low progression-free survival and low overall survival
.
Compared with tumors related to the bottom of the fourth ventricle, EZHIP and H3K27ac were higher in tumors related to the top and lateral crypts
.
These data indicate that high EZHIP protein abundance is associated with poor prognosis of PFA
.
In addition, PF ependymoma with high expression of H3K27ac and EZHIP is related to the tumor location of the top and lateral crypts of the fourth ventricle
.
According to the chip sequence analysis, the research team noticed that a key component of the AMP-activated protein kinase (AMPK) complex is closely related to the expression of EZHIP and H3K27ac
.
AMPK is a key metabolic sensor that can be activated by metformin
.
Because metformin can also inhibit the citric acid cycle, the research team concluded that metformin treatment can reduce the citric acid cycle metabolites in PFA cells
.
In addition, metformin has shown strong anti-cancer effects and is currently being tested in more than 250 cancer clinical trials
.
So the research team evaluated the sensitivity of the PFA cell line to metformin
.
The results showed that the PFA cell line was sensitive to high-dose metformin treatment, and down-regulated proteins related to glycolysis, tricarboxylic acid cycle, pyruvate metabolism, and PPP
.
In addition, metformin reduces tumor growth and EZHIP in the body, and increases H3K27me3
.
These results indicate that metformin inhibits PFA's tricarboxylic acid cycle and pentose phosphate pathway (PPP) metabolism, and down-regulates EZHIP to increase total H3K27me3, achieving the effect of inhibiting tumor growth
.
In general, this work clarified the metabolic characteristics of type A posterior fossa ependymoma (PFA), and the initiator of this metabolic characteristic-EZHIP protein
.
The drug metformin, which inhibits the glycometabolism pathway, has a significant effect, which can shrink tumors and prolong survival.
The mechanism is to inhibit EZHIP and slow down the sugar metabolism of tumors
.
This study gave people a good idea that not all tumors are caused by DNA mutations.
Posterior fossa ependymomas like this are driven by epigenetic changes, which increase tumor metabolic activity.
, The use of antimetabolites must not only directly reduce tumor metabolism, but also directly or indirectly target epigenetic materials to achieve the fundamental cure of the disease
.
Link to the paper: https:// is open for reprinting, welcome to forward to Moments and WeChat groups
