HuR/methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis.
OBJECTIVE
Hepatic de-differentiation, liver development, and malignant transformation are processes in which the levels of hepatic S-adenosylmethionine are tightly regulated by 2 genes: methionine adenosyltransferase 1A (MAT1A) and methionine adenosyltransferase 2A (MAT2A). MAT1A is expressed in the adult liver, whereas MAT2A expression primarily is extrahepatic and is associated strongly with liver proliferation. The mechanisms that regulate these expression patterns are not completely understood.


METHODS
In silico analysis of the 3' untranslated region of MAT1A and MAT2A revealed putative binding sites for the RNA-binding proteins AU-rich RNA binding factor 1 (AUF1) and HuR, respectively. We investigated the posttranscriptional regulation of MAT1A and MAT2A by AUF1, HuR, and methyl-HuR in the aforementioned biological processes.


RESULTS
During hepatic de-differentiation, the switch between MAT1A and MAT2A coincided with an increase in HuR and AUF1 expression. S-adenosylmethionine treatment altered this homeostasis by shifting the balance of AUF1 and methyl-HuR/HuR, which was identified as an inhibitor of MAT2A messenger RNA (mRNA) stability. We also observed a similar temporal distribution and a functional link between HuR, methyl-HuR, AUF1, and MAT1A and MAT2A during fetal liver development. Immunofluorescent analysis revealed increased levels of HuR and AUF1, and a decrease in methyl-HuR levels in human livers with hepatocellular carcinoma (HCC).


CONCLUSIONS
Our data strongly support a role for AUF1 and HuR/methyl-HuR in liver de-differentiation, development, and human HCC progression through the posttranslational regulation of MAT1A and MAT2A mRNAs.
Vázquez-Chantada
Mercedes
M
Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Bizkaia, Spain.
Fernández-Ramos
David
D
Embade
Nieves
N
Martínez-Lopez
Nuria
N
Varela-Rey
Marta
M
Woodhoo
Ashwin
A
Luka
Zigmund
Z
Wagner
Conrad
C
Anglim
Paul P
PP
Finnell
Richard H
RH
Caballería
Juan
J
Laird-Offringa
Ite A
IA
Gorospe
Myriam
M
Lu
Shelly C
SC
Mato
José M
JM
Martínez-Chantar
M Luz
ML
D020413:3' Untranslated Regions; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D050938:Glycine N-Methyltransferase / Q000172:deficiency / Q000235:genetics; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012436:S-Adenosylmethionine / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630988:Hnrnpd protein, rat; C000630987:Hnrpd protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012436:S-Adenosylmethionine; D050938:Glycine N-Methyltransferase; C494511:Gnmt protein, mouse; C490703:Mat1a protein, mouse; C512846:Mat2a protein, rat; D008716:Methionine Adenosyltransferase