Tomasi, Maria Lauda and Tomasi, Ivan and Ramani, Komal and Pascale, Rosa Maria and Xu, Jung and Giordano, Pasquale and Mato, José M. and Shelly, C. Lu (2012) S-adenosylmethionine regulates ubiquitin-conjugating enzyme 9 protein expression and sumoylation in murine liver and human cancers. Hepatology, Vol. 56 (3), p. 982-993. eISSN 1527-3350. Article.
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Background and rationale: Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and overexpressed in several malignancies but its expression in hepatocellular carcinoma (HCC) is unknown. Hepatic S-adenosylmethionine (SAMe) level falls in methionine adenosyltransferase 1A (Mat1a) knockout (KO) mice, which develop HCC, and in ethanol fed mice. Here we examined regulation of Ubc9 by SAMe in murine liver and human HCC, breast and colon carcinoma cell lines and specimens. Methods: Real-time PCR and Western blotting measured gene and protein expression, respectively. Immunoprecipitation followed by Western blotting examined protein-protein interactions. Results: Ubc9 expression is increased in HCC and when hepatic SAMe level falls. SAMe treatment in Mat1a KO mice reduced Ubc9 protein but not mRNA level and lowered sumoylation. Similarly, treatment of liver cancer cell lines HepG2 and Huh-7, colon cancer cell line RKO and breast cancer cell line MCF-7 with SAMe or its metabolite methylthioadenosine (MTA) reduced only Ubc9 protein level. Ubc9 post-translational regulation is unknown. Ubc9 sequence predicts a possible phosphorylation site by cell division cycle 2 (Cdc2), which directly phosphorylated recombinant Ubc9. Mat1a KO mice have higher phospho-Ubc9 level, which normalized after SAMe treatment. SAMe and MTA treatment lowered Cdc2 mRNA and protein levels, phospho-Ubc9 and protein sumoylation in liver, colon and breast cancer cells. Serine 71 of Ubc9 is required for phosphorylation, interaction with Cdc2 and protein stability. Cdc2, Ubc9 and phospho-Ubc9 levels are increased in human liver, breast and colon cancers. Conclusions: Cdc2 expression is increased and Ubc9 is hyperphosphorylated in several cancers and this represents a novel mechanism to maintain high Ubc9 protein expression that can be inhibited by SAMe and MTA.
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