A collaborative research group consisting of Professor Chiaki Takahashi and Assistant Professor Susumu Kohno of the Cancer Research Institute , Kanazawa University, and Professor Fumio Matsuda, Associate Professor Nobuyuki Okahashi, and Professor Hiroshi Shimizu of the Graduate School of Information Science, Osaka University, has discovered an entirely new mechanism by which the RB1 tumor suppressor gene (*1) controls cell differentiation (*2).
The RB1 gene has been known as a "tumor suppressor gene" that prevents the onset of cancer by suppressing abnormal progression of the cell cycle. However, this research has revealed a new function of RB1: promoting the differentiation of cancer cells and suppressing malignant progression by regulating cellular metabolism (energy usage).
The research group first established a cancer cell system (cancer cell model) in which loss of RB1 function suppresses cell differentiation and increases the malignancy (undifferentiated nature) of cancer. Further analysis revealed that the balance of a metabolic pathway called the "glycolytic system (*3)" is greatly disrupted in cells that have lost RB1. The main cause was found to be a marked decrease in the expression of PGAM (phosphoglycerate mutase, *4), an enzyme gene involved in the glycolytic pathway. This phenomenon was observed not only in cancer cells but also in normal cells that produce skeletal muscle and adipose tissue, indicating that the relationship between RB1 and PGAM may be a universal regulatory mechanism of cell differentiation.
The results of this research pave the way for new cancer treatment strategies that promote differentiation and inhibit malignant transformation by intervening in the metabolic mechanisms of cancer cells. In the future, it is expected that therapeutic strategies targeting RB1 and PGAM will be developed.
The research results were published in the online edition of the British journal Cell Death and Disease (Nature Springer) on July 24, 2025 at 23:00 (JST).
Fig. 1 Most enzymes in the glycolytic system are transcriptionally regulated by Myc, a cancer-related transcription factor, and HIF1α, a hypoxia response factor. On the other hand, only PGAM (phosphoglycerate mutase) is outside of these regulatory pathways and is specifically regulated by RB1, a cancer suppressor gene, as revealed by this study. This finding indicates a novel molecular mechanism by which RB1 promotes cell differentiation and suppresses tumorigenesis through metabolic pathways.
【Glossary】
*1 RB1 tumor suppressor gene
RB1 is a well-known tumor suppressor gene, and congenital abnormalities in the RB1 gene can lead to the development of cancers such as retinoblastoma. RB1 suppresses uncontrolled cell proliferation by suppressing the activity of genes that promote cell cycle progression and promoting cell differentiation. RB1 function is known to be reversibly or irreversibly lost in various cancers.
*2 Cell differentiation
This refers to the process by which immature cells change into functional cells with specific roles, such as muscles and nerves. In cancer, this differentiation process is thought to be inhibited, resulting in undifferentiated, highly proliferative malignant cells.
*3 Glycolytic system
This is the basic metabolic pathway by which cells break down sugar (glucose) to produce ATP (adenosine triphosphate) as a source of energy. In cancer cells, this pathway is often abnormally activated, known as the "Warburg effect".
*4 Phosphoglycerate mutase (PGAM)
One of the enzymes involved in the glycolytic system, PGAM plays an important role in the intermediate step of glucose metabolism. It is an essential enzyme in regulating energy production and the metabolic balance of cells.
Click here to see the press release【Japanese only】
Journal Cell Death and Disease
Researcher Information: Chiaki Takahashi, Susumu Kono
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