Loss of IGF2BP3 reduces RNA methylation, revealing its role in regulating genes and rewiring metabolism to control RNA.
Cancer cells continuously grow and divide, often rely on glycolysis, a metabolic energy pathways and RNA regulation to maintain their chemical environment, identified by researchers at the UCLA Health Jonsson Comprehensive Cancer Centre. ()
IGF2BP3, a single protein connects both RNA modification and glycolysis in leukemia.
The protein switches inefficient and fast glycolysis pathways, while altering RNA regulation that propel protein production helping leukemia cells multiply and survive.
The discovery underscores IGF2BP3 protein as ‘master switch’ as this unites both separate processes (RNA regulation and glycolysis pathways) for cancer cells. These insights pave way for new treatments, as other cancers may follow same tracks for survival.
Deciphering Cancer’s Energy Source
“We expected IGF2BP3 might control RNA, but what we weren’t expecting was how strongly it also reshaped metabolism,” said Dr. Dinesh Rao, professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA and senior author of the study.
“That connection hadn’t been seen before and could be critical to how cancer cells gain their advantage. By uncovering this link, we now have a clearer picture of how leukemia sustains itself. If we can block this rewiring, we might be able to cut off both the energy supply and the survival signals cancer cells rely on.”
The Role of IGF2BP3 in Leukemia’s Survival
Rao and his lab have been studying IGF2BP3 for nearly a decade and found that it is essential for the survival of leukemia cells. The protein belongs to a family of RNA-binding proteins that are normally active only at the earliest stages of human development.
After birth, their activity largely shuts down, but in some cancers — including leukemia, brain tumors, sarcomas, and breast cancers — IGF2BP3 switches back on.
The team has previously shown that IGF2BP3 is essential for an especially aggressive subtype of pediatric acute lymphoblastic leukemia. Mice engineered to lack the protein were resistant to developing leukemia, yet remained otherwise healthy, suggesting IGF2BP3 is uniquely tied to cancer biology.
Blocking the IGF2BP3 Protein May Disrupt Glycolysis
The rewiring of cellular metabolism has long been a central focus in cancer research, and Rao’s team began to explore whether IGF2BP3 also shapes how leukemia cells process energy.
To understand how IGF2BP3 influences these processes, Rao and his team used a specialized technology called the Seahorse assay, which measures how cells use oxygen and produce acid, essentially putting cells “on a treadmill” to see how they burn energy.
They found when leukemia cells were stripped of IGF2BP3, their preferred energy pathway, glycolysis, dropped sharply. Glycolysis is a quick but wasteful way of breaking down sugar, often favored by cancer cells because it produces the building blocks they need to multiply.
Tracking IGF2BP3’s Influence on Cellular Chemistry
Further experiments traced how sugar was being processed inside the cell. The team discovered that levels of S-adenosyl methionine, or SAM, a critical molecule that donates chemical tags used to modify RNA, fell dramatically without IGF2BP3.
As a result, the number of RNA methylation marks also decreased, revealing that IGF2BP3 doesn’t just regulate genes, but also rewires metabolism in ways that feed back into RNA control.
As a final step, the researchers used specially engineered mice that lacked the IGF2BP3 gene. When they reintroduced the human version of the protein, the changes in metabolism and RNA regulation returned, confirming IGF2BP3’s central role in driving these processes.
“These experiments revealed a chain reaction,” said Dr. Gunjan Sharma, a postdoctoral scholar in the Rao laboratory. “When we removed IGF2BP3, it didn’t just change how cells used energy. It also disrupted their chemical balance and the way their RNA was regulated.”
“That’s how we realized IGF2BP3 links metabolism and RNA control in leukemia.”
Beyond Energy How IGF2BP3 Helps Sustain Cancer Cell Growth
The findings suggest that IGF2BP3 allows leukemia cells to take a less efficient metabolic pathway not because it provides more energy, but because it supplies building blocks and RNA modifications that reinforce cancer cell survival.
“In a way, IGF2BP3 is a master planner,” Sharma explained. “It rewires both energy use and RNA control to keep leukemia cells growing where normal cells wouldn’t.”
While the study focused on leukemia, the researchers believe the implications may extend to many other cancers.
“While leukemia is the model where we’re seeing this most clearly, the broader message is that cancer cells across the board may be using similar strategies,” said Rao, who is a member of the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research at UCLA.
IGF2BP3 Protein Can Function as a Biomarker for Targeting Treatments
“This means the insights from our research could eventually help us design therapies that target not only leukemia but also other cancers that exploit the same pathways.”
High levels of IGF2BP3 could also serve as a biomarker, the researchers noted, helping to identify cancers that may respond to therapies disrupting RNA modifications or SAM production.
Rao’s lab is now testing small molecules that block IGF2BP3, with the most promising strategies likely pairing these inhibitors with drugs that interfere with cancer metabolism.
References:
- IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA Methylation – (https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01101-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124725011015%3Fshowall%3Dtrue )
Source-Eurekalert