S-adenosylmethionine regulates apurinic/apyrimidinic endonuclease 1 stability: implication in hepatocarcinogenesis.
OBJECTIVE
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.
Tomasi
Maria Lauda
ML
Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, California, USA.
Iglesias-Ara
Ainhoa
A
Yang
Heping
H
Ramani
Komal
K
Feo
Francesco
F
Pascale
Maria Rosa
MR
Martínez-Chantar
M Luz
ML
Mato
José M
JM
Lu
Shelly C
SC
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012436:S-Adenosylmethionine / Q000378:metabolism*; D014162:Transfection
D012436:S-Adenosylmethionine; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase