Mol Cell: revealed that two transcription factors globally inhibit acetyl-CoA production and thus promote liver cancer

The causes of liver cancer are manifold
.
In addition to the metabolic disorders associated with obesity, the main causes in the Western world are hepatitis C virus infection and heavy alcohol consumption
.
Although hepatocellular carcinoma (one of the liver cancers) is relatively rare compared to other types of cancer, it is one of the leading causes of
cancer-related death due to poor prognosis.

Like all tumor cells, liver cancer cells proliferate
rapidly in an uncontrolled manner.
This requires a fundamental change in their metabolism
.
In a new study, Professor Michael N.
Hall of the University of Basel Biology Center in Switzerland and his research team now report that liver cancer cells reduce the production
of a central metabolic molecule.
In this way, global metabolism is altered, allowing tumor cells in the liver to grow
faster.
The findings were published in the November 17, 2022 issue of the journal Molecular Cell under the title "Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis.
"

The liver is the largest metabolic organ
in our body.
It processes and stores nutrients and detoxifies
harmful compounds.
When healthy liver cells become cancerous, it loses its normal function
.
Co-author Dr.
Dirk Mossmann, a cancer researcher at the University of Basel's Centre for Bioscience, explains: "Tumour cells are selfish
.
They change their metabolism in order to grow
as fast as possible.
At the same time, however, they no longer perform their tasks
as liver cells.
This is why liver function is impaired
in patients with hepatocellular carcinoma.
”

Major changes in cellular metabolism

The acetyl-CoA molecule plays a central role
in cellular metabolism.
On the one hand, it is the end product of many degradation pathways; On the other hand, it is necessary to
produce or chemically modify a large number of other molecules.
Dr.
Sujin Park, first author of the paper, explains, "We found that all acetyl-CoA biosynthetic pathways are downregulated in hepatoma cells
.
This leads to a decrease in acetyl-CoA, which in turn affects many other proteins, including metabolic enzymes
.
These enzymes are functionally altered because they are no longer modified
by acetyl-CoA.
This can help tumor cells, for example, convert sugar into energy
more efficiently.
”

Image from Molecular Cell, 2022, doi:10.
1016/j.
molcel.
2022.
10.
027
.

Another effect is that acetyl-CoA affects cell differentiation
.
The decrease in acetyl-CoA levels promotes the dedifferentiation of hepatocytes
.
In other words, they are reprogrammed into early, immature stages of development
.
They lose their characteristic function and begin to split
rapidly.

Mossmann said, "We wanted to know how all acetyl-CoA metabolic pathways might be inhibited
in tumor cells.
" The answer is found in the --- of two proteins called transcription factors--- TEAD2 and E2A, which regulate a wide range of genes that trigger a wide range of metabolic changes
.
”

Cancer with specific metabolic characteristics

These authors observed this mechanism
in liver tumors in mice and patients.
Samples of the patient's liver tumour were obtained
from Professor Markus Heim from the Department of Biomedical Sciences of the University of Basel and the University Hospital Basel.

Park said, "These two transcription factors have been shown to actually play a key role--- inhibiting them in mice can stop tumorigenesis
.
" In addition, metabolic changes in liver tumor cells exhibit a 'signature' that can also be found
in other types of cancer, such as prostate and pancreatic cancer.
”

This metabolic cancer feature also provides information
about disease progression.
It is associated with
poor survival.
One of the biggest problems is that liver cancer is asymptomatic for a long time, so the disease is often detected
at an advanced stage.
Surgical removal or liver transplantation is often no longer a treatment option
.
Therefore, an intriguing question is when this cancer feature arises and whether it can be used as a biomarker for screening and early diagnosis
of liver cancer.
(Biovalley Bioon.
com)

Resources:

Sujin Park et al.
 Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis, Molecular Cell, 2022, doi:10.
1016/j.
molcel.
2022.
10.
027.