SALL3 interacts with DNMT3A and shows the ability to inhibit CpG island methylation in hepatocellular carcinoma.
The mechanisms of aberrant CpG island methylation in oncogenesis are not fully characterized. In particular, little is known about the mechanisms of inhibition of CpG island methylation. Here we show that sal-like 3 (SALL3) is a novel inhibitory factor for DNA methyltransferase 3 alpha (DNMT3A). SALL3 binds to DNMT3A by a direct interaction between the double zinc finger motif of SALL3 and the PWWP domain of DNMT3A. SALL3 expression reduces DNMT3A-mediated CpG island methylation in cell culture and in vitro. CpG island methylation is enhanced in SALL3-depleted cells. Consistently, DNMT3A from SALL3-depleted cells increases methyltransferase activity in vitro. Binding of DNMT3A to chromatin is reduced or increased by SALL3 expression or depletion, respectively, accounting for the mechanism by which SALL3 inhibits DNMT3A-mediated CpG island methylation. We also show that SALL3 is inducible by BMP-4 and silenced by associated DNA methylation in hepatocellular carcinoma (HCC). Our results suggest that silencing of SALL3 results in acceleration of DNA methylation in HCC. This functional characterization of SALL3 sheds light on regulatory mechanisms for DNMT3A and provides new strategies to inhibit aberrant methylation in cancer.
Shikauchi
Yuko
Y
Department of Epigenetic Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan.
Saiura
Akio
A
Kubo
Takahiko
T
Niwa
Yasuharu
Y
Yamamoto
Junji
J
Murase
Yaeko
Y
Yoshikawa
Hirohide
H
D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D055415:Bone Morphogenetic Protein 4; D002843:Chromatin; C000717967:DNMT3A protein, human; D018398:Homeodomain Proteins; C484466:SALL3 protein, human; D014157:Transcription Factors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A