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Molecular and Cellular Biology, April 2009, p. 1944-1958, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.00840-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

SALL3 Interacts with DNMT3A and Shows the Ability To Inhibit CpG Island Methylation in Hepatocellular Carcinoma{triangledown} ,{dagger}

Yuko Shikauchi,1 Akio Saiura,2 Takahiko Kubo,1 Yasuharu Niwa,1 Junji Yamamoto,2 Yaeko Murase,1 and Hirohide Yoshikawa1*

Department of Epigenetic Carcinogenesis,1 Department of Surgery, The Cancer Institute, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan2

Received 25 May 2008/ Returned for modification 26 June 2008/ Accepted 2 January 2009

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.

* Corresponding author. Mailing address: Department of Epigenetic Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan. Phone: 81-3-3570-0447. Fax: 81-3-3570-0230. E-mail: hirohide.yoshikawa{at}jfcr.or.jp

{triangledown} Published ahead of print on 12 January 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2009, p. 1944-1958, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.00840-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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