Nat Commun: The hepatocellular nuclei factor 4A regulates the metabolism of thiohampheal and determines the sensitivity of liver cancer to methionine limits.

As a sulfur-containing amino acid, methionine is an essential amino acid in the human body and can only be obtained from food, especially animal proteins.
have shown that limiting methionine not only has the effect of prolonging life, reducing fat and enhancing insulin sensitivity in animals, but may also inhibit a variety of cancers.
, however, different cancer cells have different dependences on methionine and different reactions to methionine restrictions, the molecular mechanism of which is not clear.
liver is the main organ for metabolism of sulfur-containing amino acids, responsible for metabolism of more than 50% of the food source methionine.
Through the liver adenosine transferase 1A (MAT1A), methionine entering the liver is converted into S-adenosine methionine, then transmethylated and hydrolyzed reactions to form the same type of cysteine, and then methyl glycine-cysteine S-methyl transferase (BHMT) catalytic return of its methylation to methionine.
homocysteine can also enter the transsulfurization pathway, forming cysulphether, cysteine, and hydrogen sulfide through the cysulphate beta synthase (CBS) and the cysulpheal ether gamma lysase (CTH).
can also be used to produce also prototype glutathione, or to form taurine by cysteine double oxygenase (CDO1).
, methionine is not only used in protein synthesis, but also in regulating the metabolism of sulfur-containing amino acids, maintaining the steady state of redox and signal conduction.
study found that many metabolic enzymes associated with sulfur-containing amino acids showed a decrease in expression in liver tumors, and that this decline was associated with the malignancy of tumors and poor prognosis.
The imbalance in the metabolism of thiamine in liver cancer means that methionine restriction may be a potential treatment for liver cancer, but it is not yet understood whether the molecular mechanism of this disorder can be used for liver cancer treatment or increase the sensitivity of existing therapies.
August 7, 2020, xiaoling Li of the National Institutes of Health's Institute of Environmental Health Sciences (NIEHS) team, together with Leping Li, director of the Institute of Biostattics and Computational Biology, and Ja, Director of Mass Spectrometling Platform Johnson Williams, along with Professor Jason Locasale of Duke University and Professor Xuemei Tong of Shanghai Jiaoda University School of Medicine, published a research paper in the journal Nature Communications entitled HNF4 alpha regulates susso amino acid metabolism and confers sensory to methionine restriction in liver cancer.
the study revealed the relationship between sulfur-containing amino acid metabolism and hepatocellular nuclei factor 4A (HNF4 alpha) through a series of biological information, molecular and metabolic analyses, as well as cell and mouse experiments.
HNF4 alpha is an important transcription factor in the liver, regulating the expression of various liver genes and determining the functional properties of liver cells and liver.
HNF4 alpha expression declines in liver cancer and is widely believed to be a tumor suppressor gene and may inhibit intersessional transformation (EMT).
study showed that HNF4 alpha regulates the metabolism of sulfur-containing amino acids and plays a decisive role in the sensitivity of liver cancer to methionine limits.
researchers, through clustering analysis of liver cancer cells and tumor databases, confirmed that in liver cancer, sulfur-containing amino acid metabolic enzymes, including MAT1A, BHMT, CBS, CTH, and CDO1, were positively correborated with HNF4 alpha and negatively cored with interstitrinal cell marker proteins.
chromatin immunorecipitation and luciferase reporting experiments showed that HNF4 alpha regulates the transcription of metabolic enzymes containing thiomersal acids.
Compared to endothyl liver cancer cells rich in HNF4 alpha, interstitial liver cancer cells barely express HNF4 alpha, have different sulfur-containing amino acid metabolites in the cells, and show resistance to methionine restrictions and cell death caused by Sorofenib.
Knocking out HNF4 alpha in endosulpheric liver cancer cells directly leads to a decrease in sulfur-containing amino acid metabolases, and the metabolism of thiamine-containing amino acids in cells becomes similar to that of interstite liver cancer cells, especially when compared to non-knocking cells, the content of trans-sulfur pathline products, including cysulfur ether, taurine and hydrogen sulfide, decreased significantly.
, there was a decrease in the expression of the endotourmark gene, an increase in interstitial marker gene expression, an increase in cell migration, and increased resistance to methionine restriction and cell death caused by Sorofenib.
mouse tumor transplantation experiments also showed that low methionine food inhibited the growth of endoskin cancer cell tumors, but did little to remove HNF4 alpha endosulpheric liver cancer cell tumors.
addition, knocking out a single sulfur-containing amino acid metabolase in an endostrophic liver cancer cell is similar to knocking out HNF4 alpha in terms of EMT, cell migration, and resistance.
, the restoration of the transsulfurization path from genetic and metabolic aspects significantly mitigates the effects of HNF4 alpha deficiency.
study suggests that dietary restrictions on methionine intake, whether used alone or in association with Soorofenib, may have therapeutic effects on liver cancer.
HNF4 alpha expression levels in patients' tumors can be used as biological indicators to predict sensitivity to methionine restrictions and to screen candidates for clinical trials.
was conducted in collaboration with the National Institutes of Health's Institute of Environmental Health Sciences, Duke University and Shanghai Jiaoda University School of Medicine.
senior researcher at the Metabolic Gene Environment Research Group at the National Institutes of Health's Institute for Environmental Health Sciences, was the lead correspondent, with Bigologist Qing Xu as the lead author and Staff Scientist Igor Shats as co-author.
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