The cytosolic role of EZH2-IMPDH2 complex in melanoma progression and metastasis via GTP regulation

Although conventional EZH2 enzymatic inhibitors have shown preclinical efficacy in various tumors, here we demonstrated that B-Raf mutant melanoma cells do not respond effectively to pharmacological inhibition of EZH2 in vitro . Based on our LC-MS and biochemical assays, N-terminal of cytosolic EZH2 interacts with IMPDH2 through the IMPDH2-CBS domain in a PRC2- and methylation-independent (MTI) manner. Cytosolic EZH2 induces cytosolic accumulation of IMPDH2 and increases its tetramerization (activity). EZH2 upregulates cellular GTP levels via IMPDH2 activation and guanosine rescues siEZH2-reduced clonogenicity/invasion phenotype by regulating rRNA metabolism and Rho GTPase activity. Sappanone A by reducing the EZH2/IMPDH2 interaction and IMPDH2 tetramerization attenuates the growth/invasion abilities of a range of cancers including, cutaneous / uveal melanoma, breast, prostate, ovarian cancer in vitro, but has no cytotoxic effect on melanocytes or bone marrow progenitor cells. These results point to a MTI, but GTP-mediated non-canonical mechanism of EZH2 in melanoma progression and metastasis. Highlights ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes