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Updated: Jul 4, 2026
07:41
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Cytosolic EZH2-IMPDH2 complexes regulate melanoma progression and metastasis via GTP
Gamze Kuser-Abali1, Fumihito Noguchi1, Peinan Zhao1
1Department of Cancer Medicine, Monash University, Melbourne, VIC 3004, Australia.
Molecular Cell
|July 2, 2026
Summary
Enhancer of zeste homolog 2 (EZH2) has a novel, non-enzymatic role in cancer. EZH2 interacts with IMPDH2 to boost GTP synthesis, driving tumor growth through a pathway independent of its methyltransferase activity.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Enhancer of zeste homolog 2 (EZH2) functions as a methyltransferase, catalyzing histone H3K27 trimethylation via the polycomb repressive complex 2.
- The anti-cancer efficacy of inhibiting EZH2's methyltransferase activity has shown variable results, suggesting alternative oncogenic mechanisms.
- EZH2's role in cancer progression extends beyond its canonical epigenetic functions.
Purpose of the Study:
- To investigate a methyltransferase-independent mechanism of EZH2 in cancer.
- To identify novel protein interactions and cellular pathways regulated by EZH2.
- To explore potential therapeutic strategies targeting EZH2's non-epigenetic functions.
Main Methods:
- Mass spectrometry was employed to identify protein interactions between EZH2 and inosine monophosphate dehydrogenase 2 (IMPDH2).
- EZH2 knockdown and IMPDH2 knockout models were utilized to assess functional consequences.
- Guanosine-5'-triphosphate (GTP) levels, ribosome biogenesis, and tumor progression were evaluated in vitro and in vivo. Analysis of human melanoma and pan-cancer datasets for EZH2 and IMPDH2 expression and localization.
Main Results:
- EZH2 directly interacts with IMPDH2 in the cytoplasm through its EED-binding domain and IMPDH2's CBS domain, independent of its methyltransferase activity.
- EZH2 knockdown reduced IMPDH2 levels, GTP synthesis, and ribosome biogenesis, consequently impairing cancer progression. These effects were reversed by guanosine supplementation.
- IMPDH2 knockout counteracted EZH2's tumor-promoting effects. Increased cytosolic EZH2 and IMPDH2 expression correlated with nucleolar enlargement in human melanomas and were observed across multiple cancers. Sappanone A, an inhibitor of the EZH2-IMPDH2 interaction, demonstrated anti-tumorigenic properties.
Conclusions:
- EZH2 possesses a novel oncogenic function mediated by its interaction with IMPDH2, promoting GTP synthesis and cancer progression independently of its methyltransferase activity.
- The EZH2-IMPDH2 complex represents a potential therapeutic target for various cancers.
- Targeting this methyltransferase-independent pathway offers a new avenue for cancer treatment strategies.
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