One of the most widely used chemotherapeutic agents for colorectal cancer is 5-fluorouracil (5-FU), a cornerstone treatment that has improved outcomes for countless patients. However, repeated treatments develop drug resistance, allowing cancer cells to adapt and gradually evade the effects of treatment.
In many patients, tumors initially respond well to treatment but later develop resistance, ultimately leading to treatment failure and disease recurrence. Despite its clinical importance, the molecular mechanisms that allow cancer cells to tolerate 5-FU therapy remain poorly understood.
A research team led by Dr. Cho Hyun-soo of the Korea Research Institute of Biological Sciences (KRIBB) Stem Cell Convergence Research Center, in collaboration with Professor Heo Geun of Kyungpook National University, identified an important mechanism underlying 5-FU resistance in colorectal cancer and proposed a new therapeutic strategy to restore tumor sensitivity to treatment.
To investigate how resistance develops, the researchers generated colorectal cancer cells that survived repeated exposure to 5-FU and compared them to non-resistant cancer cells. Their analysis revealed a significant increase in the activity of EHMT2, a protein involved in regulating gene expression through epigenetic mechanisms. The research team hypothesized that EHMT2 may play a central role in chemotherapy resistance.
Analysis of patient datasets supported this conclusion. Patients with elevated EHMT2 activity had a worse response to 5-FU treatment and lower overall survival, indicating a strong association between EHMT2 activation and unfavorable clinical outcomes.
The researchers next investigated whether suppressing EHMT2 could reverse resistance. When EHMT2 activity was inhibited, previously resistant cancer cells regained sensitivity to 5-FU, increasing cancer cell death and significantly reducing tumor cell proliferation. In contrast, artificially increasing EHMT2 expression in non-resistant cells enhanced resistance to chemotherapy.
These findings demonstrate that EHMT2 functions as an important regulator of chemotherapy resistance and that targeting this protein may restore resistant cancer cells to a treatment-responsive state.
To determine whether this strategy is also effective in clinically relevant settings, the team conducted additional validation studies using patient-derived colorectal cancer organoids and animal models. Combining 5-FU with an EHMT2 inhibitor significantly inhibited the growth of previously treatment-resistant colorectal tumors.
The results suggest that it may be possible to improve the effectiveness of existing treatments without developing entirely new anticancer drugs. Rather, reducing cancer cell resistance may restore the therapeutic benefits of established treatments and provide new strategies to overcome chemoresistance.
This study is important because it uncovered a previously unrecognized mechanism by which cancer cells adapt to chemotherapy and identified a promising therapeutic target that could reverse the process. This finding could have implications beyond colorectal cancer and could also have implications for other cancers commonly treated with 5-FU, such as stomach, pancreatic, and breast cancer.
This study shows that the epigenetic regulatory protein EHMT2 plays an important role in the process by which cancer cells adapt to chemotherapy. Targeting EHMT2 may provide a new therapeutic approach to overcome drug resistance and increase the efficacy of existing anticancer treatments. ”
Dr. Cho Hyun-soo, AS Principal Researcher
The Korea Research Institute of Biological Sciences (KRIBB) is South Korea’s leading national research institute dedicated to cutting-edge research in biotechnology and life sciences. Founded in 1985, KRIBB focuses on advancing scientific knowledge in areas such as molecular biology, genomics, bioinformatics, synthetic biology, and aging-related research. As a government-funded research institute, KRIBB plays a vital role in driving innovation, supporting national research and development strategies, and collaborating with national and international academic and industrial partners.
This research was supported by the KRIBB Key Research Program, the KRIBB Strategic Research Program, and the Bio and Medical Technology Development Program of the Ministry of Science, Information and Communications.
The study was published online on May 18 in Signal Transduction and Targeted Therapy (impact factor: 52.7), one of the world’s leading academic journals in translational medicine and targeted therapeutics.
The title of this article is “Targeting EHMT2 overcomes 5-fluorouracil resistance in colorectal cancer by regulating cell cycle and apoptosis.”
Corresponding authors are Keun Hur of Kyungpook University, Tae-Su Han, Dae-Soo Kim, Mi-Young Son, and Hyun-Soo Cho of Korea Research Institute of Biological Sciences (KRIBB). The lead author is In Hwan Tae from KRIBB.
sauce:
National Science and Technology Research Council
Reference magazines:
Te, IH, others. (2026). Targeting EHMT2 overcomes 5-fluorouracil resistance in colorectal cancer by regulating cell cycle and apoptosis. Signal transduction and targeted therapy. DOI: 10.1038/s41392-026-02692-7. https://www.nature.com/articles/s41392-026-02692-7
