Cytosolic EZH2-IMPDH2 complexes regulate melanoma progression and metastasis via GTP

Kuser-Abali, G; Noguchi, F; Zhao, P; Szeto, P; Zhang, Y; Huang, C; Barlow, CK; Pomilio, G; Boudes, M; Chew, C; Moghaddam, SM; Leece, I; Cheung, JG; Ameratunga, M; Wong, NC; Andrews, MC; Schittenhelm, RB; Wei, A; Naranbhai, V; Davidovich, C; Shackleton, M

Author(s): Kuser-Abali, G; Noguchi, F; Zhao, P; Szeto, P; Zhang, Y; Huang, C; Barlow, CK; Pomilio, G; Boudes, M; Chew, C; Moghaddam, SM; Leece, I; Cheung, JG; Ameratunga, M; Wong, NC; Andrews, MC; Schittenhelm, RB; Wei, A; Naranbhai, V; Davidovich, C; Shackleton, M;
Details: Publication Year 2026-07-02,Volume 86,Issue #13,Page 2521-2538.e10
Journal Title: Molecular Cell
Abstract: Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that tri-methylates histone H3K27 as the catalytic subunit of the polycomb repressive complex 2. However, inhibition of EZH2 methyltransferase showed only variable anti-cancer efficacy, suggesting that this approach is insufficient. Here, we demonstrate a methyltransferase-independent mechanism of EZH2 wherein EZH2 interacts with inosine monophosphate dehydrogenase 2 (IMPDH2) in the cytoplasm to promote guanosine-5'-triphosphate (GTP) synthesis. Mass spectrometry identified methyltransferase-independent interactions between the EED-binding domain of EZH2 and the CBS domain of IMPDH2. EZH2 knockdown impeded IMPDH2 and reduced GTP levels, ribosome biogenesis, and cancer progression-effects reversed by guanosine. IMPDH2 knockout antagonized EZH2's tumor-promoting effects in vivo, and increased cytosolic EZH2 and IMPDH2 expression was observed in human melanomas and associated with nucleolar enlargement. EZH2-IMPDH2 complexes were also observed across multiple cancers, wherein Sappanone A (SA), which inhibits EZH2-IMPDH2 interactions, was anti-tumorigenic. These findings reveal a methyltransferase-independent oncogenic mechanism of EZH2.
Publisher: Cell Press
Keywords: *Enhancer of Zeste Homolog 2 Protein/metabolism/genetics; Humans; *IMP Dehydrogenase/metabolism/genetics; Animals; *Melanoma/genetics/pathology/metabolism/drug therapy/enzymology; *Guanosine Triphosphate/metabolism; Cell Line, Tumor; Disease Progression; Cytosol/metabolism; Neoplasm Metastasis; Gene Expression Regulation, Neoplastic; Cell Movement; Mice; Cell Proliferation; Ezh2; GTP metabolism; Impdh2; Sappanone A; actomyosin contractility; cancer; cell motility; melanoma; ribosome biogenesis
Research Division(s): Blood Cells and Blood Cancer
PubMed ID: 42392044
Publisher's Version: https://doi.org/10.1016/j.molcel.2026.06.003
Open Access at Publisher's Site: https://doi.org/10.1016/j.molcel.2026.06.003.
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-09 08:59:09

Last Modified: 2026-07-09 08:59:18