Tomasi, Maria Lauda and Iglesias-Ara, Ainhoa and Yang, Heping and Ramani, Komal and Feo, Francesco and Pascale, Rosa Maria and Martínez-Chantar, M. Luz and Mato, José M. and Lu, Shelly C. (2009) S-adenosylmethionine regulates apurinic/apyrimidinic endonuclease 1 stability: implication in hepatocarcinogenesis. Gastroenterology, Vol. 136 (3), p. 1025-1036. ISSN 0016-5085. Article.
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Background and Aims. Genomic instability participates in the pathogenesis of hepatocellular carcinoma (HCC). Apurinic/apyrimidinic endonuclease 1 (APEX1) participates in the base excision repair of premutagenic apurinic/apyrimidinic (AP) sites. Mice deficient in methionine adenosyltransferase 1a (Mat1a KO) have chronic hepatic deficiency of S-adenosylmethionine (SAMe) and increased oxidative stress, and develop HCC. We examined livers of Mat1a KO mice for genomic instability and dysregulation of APEX1.
Methods. Studies were conducted using Mat1a KO mice livers and cultured mouse and human hepatocytes.
Results. Genomic instability increased in the livers of 1-month-old Mat1a KO mice, compared with wild-type mice, whereas Apex1 mRNA and protein levels were reduced by 20% and 50%, respectively, in Mat1a KO mice of all ages. These changes correlated with increased numbers of AP sites and reduced expression of Bax, Fas, and p21 (all APEX targets). When human and mouse hepatocytes were placed in culture, transcription of MAT1A mRNA decreased whereas that of APEX1 and c-MYC increased. However, the protein levels of APEX1 decreased to 60% of baseline. Addition of 2 mmol/L SAMe prevented increases in APEX1 and c-MYC mRNA levels, as well as decreases in MAT1A expression and cytosolic and nuclear APEX1 protein levels.
Conclusions. By 1 month of age, genomic instability increases in livers of Mat1a KO mice, possibly due to reduced APEX1 levels. Although SAMe inhibits APEX1 transcription, it stabilizes the APEX1 protein. This novel aspect of SAMe on APEX1 regulation might explain the chemopreventive action of SAMe and the reason that chronic SAMe deficiency predisposes to HCC.
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