A Single RNA Modification Topples Cancer Cells' 'Antioxidant Shield' [Reading Science]

Professor Jaeseok Noh's Team at Yonsei University Identifies a Therapeutic Vulnerability in Pancreatic Cancer via the METTL3-HNF1B Regulatory Axis

The molecular reason why cancer cells can survive even in extreme oxidative stress environments has been revealed to lie in the 'small chemical tags' attached to ribonucleic acid (RNA). The research team led by Professor Jaeseok Noh of the Department of Biochemistry at Yonsei University has identified that RNA modification (m6A) regulates a key transcription factor that maintains the antioxidant defense system of cancer cells, thus providing a clue for a new anticancer strategy.

Professor Jaeseok Noh's team published their findings in the international journal "Nucleic Acids Research," reporting that the m6A (N6-methyladenosine) modification, which binds to RNA, enables the oxidative stress defense and survival of cancer cells by maintaining the expression of the transcription factor HNF1B.

Conceptual diagram revealing the mechanism by which RNA modification regulates the 'oxidative stress defense system' of cancer cells. Provided by the research team

Pancreatic cancer is a representative intractable cancer, characterized by an extremely poor prognosis due to a very short average survival period after diagnosis, rapid development of drug resistance, and frequent recurrence. Recent studies have focused on the fact that pancreatic cancer cells survive under high oxidative stress conditions through metabolic reprogramming and a robust antioxidant system. As a result, there have been ongoing attempts to target the unique redox regulatory mechanisms of cancer cells as new therapeutic targets.

Targeting the 'RNA Stage' Instead of Transcription Factors

Transcription factors are key proteins that simultaneously regulate the expression of numerous genes, but they are structurally difficult to target directly with drugs due to the lack of a clear binding site. To overcome this limitation, the research team focused on the RNA stage, which produces the transcription factor, rather than the transcription factor itself.

The study revealed that the RNA methyltransferase complex, composed of METTL3 and METTL14, forms the m6A modification in the 3′-untranslated region (3′-UTR) of HNF1B mRNA, and this chemical tag is essential for the stability and maintenance of HNF1B expression and function. In other words, the small chemical tag attached to RNA was supporting the existence of the transcription factor HNF1B.

Antioxidant Defense Collapses with Decreased m6A

The research team analyzed the changes that occurred when the METTL3 gene was deleted or its function was inhibited, thereby reducing the m6A modification. As a result, glutathione metabolism regulated by HNF1B was significantly weakened, and the antioxidant capacity of cancer cells dropped sharply.

Reduced glutathione (GSH) levels decreased, while oxidized glutathione (GSSG) levels increased, disrupting the intracellular redox balance. Reactive oxygen species accumulated, making cancer cells extremely vulnerable to oxidative stress. These changes greatly increased the likelihood of cell death.

The research team also confirmed that directly inhibiting HNF1B function induced a similar increase in oxidative stress and cell death as observed with decreased m6A. This phenomenon was observed not only in pancreatic cancer but also in various other cancer cell types, suggesting that HNF1B may be a key transcription factor regulating antioxidant defense across cancers.

Research team photo. From the left, Jaeseok Noh, Professor of Biochemistry at Yonsei University, Minji Park, Graduate Student. Courtesy of Yonsei University

Tumor Growth Suppression Confirmed in Animal Models

In animal model experiments, tumors with inhibited METTL3 or HNF1B function showed slower growth rates and increased markers of oxidative damage. This supports the idea that the METTL3-HNF1B regulatory axis plays an important role in tumor growth and survival in vivo.

This study presents a connection in which epitranscriptomic information, such as RNA modifications, regulates the expression and function of transcription factors, thereby maintaining the metabolic homeostasis and survival strategies of cancer cells. The research team defined the METTL3-HNF1B axis as a new 'metabolic vulnerability' of cancer and proposed the potential for developing next-generation anticancer therapies that utilize m6A regulatory mechanisms.

Professor Jaeseok Noh stated, "This research demonstrates at the molecular level how small chemical tags attached to RNA support the survival strategies of cancer cells," adding, "It could be expanded as a new therapeutic approach that disrupts the oxidative stress defense system that cancer cells rely on."

The results of this study were published online on January 6 under the title "Systemic control of HNF1B-driven redox homeostasis by N6-adenosine methylation."

This research was conducted with Minji Park, an integrated master's and doctoral student in the Department of Biochemistry at Yonsei University, as the first author, and was supported by the National Research Foundation of Korea's Mid-career Researcher Program, the Yuhan Corporation YIP Program, and the BK21 Program.