Implication of human N-alpha-acetyltransferase 5 in cellular proliferation and carcinogenesis.
The N-alpha-acetyltransferase NatB, composed in Saccharomyces cerevisiae by the Nat3p and Mdm20p subunits, is an important factor for yeast growth and resistance to several stress agents. However, the expression and functional role of the mammalian counterpart has not yet been analysed. Here, we report the identification of Nat3p human homologue (hNAT5/hNAT3) and the characterization of its biological function. We found that hNAT5/hNAT3 silencing in HeLa cells results in inhibition of cell proliferation and increased sensitivity to the pro-apoptotic agent MG132. Moreover, inhibition of hNAT5/hNAT3 expression induces p53 activation and upregulation of the antiproliferative protein p21(WAF1/CIP1). The changes of the cellular transcriptome after hNAT5/hNAT3 knockdown confirmed the involvement of this protein in cell growth and survival processes. Among the genes differentially expressed, we observed upregulation of several p53-dependent antiproliferative and pro-apoptotic genes. In the c-myc transgenic mice, which is a model of inducible hepatocarcinoma, we found that hNAT5/hNAT3 was upregulated when the tumour was induced. In accordance with this observation, we noticed increased hNAT5/hNAT3 protein level in neoplastic versus non-neoplastic tissue in a high proportion of patients with hepatocellular carcinoma. Consequently, our results suggest that hNAT5/hNAT3 is required for cellular proliferation and can be implicated in tumour growth.
Ametzazurra
A
A
Division of Hepatology and Gene Therapy, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Larrea
E
E
Civeira
M P
MP
Prieto
J
J
Aldabe
R
R
D000123:Acetyltransferases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D007976:Leupeptins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde