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Carcinogenesis Advance Access published online on August 13, 2008
Carcinogenesis, doi:10.1093/carcin/bgn194
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Adiponectin stimulates Wnt inhibitory factor-1 expression through epigenetic regulations involving the transcription factor specificity protein 1

Jing Liu1,2,3, Janice BB Lam1,2,3,5,*, Kim HM Chow1,2,3, Aimin Xu1,2,3, Karen SL Lam2,3, Randall T Moon4 and Yu Wang1,3,**

1 Department of Pharmacology, University of Hong Kong, Hong Kong, China
2 Department of Medicine, University of Hong Kong, Hong Kong, China
3 Research Center of Heart, Brain, Hormone, and Healthy Aging, University of Hong Kong, Hong Kong, China
4 Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, USA
5 School of Biological Sciences, University of Auckland, Auckland, New Zealand

** Address correspondence to: Yu Wang, Department of Pharmacology, University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Rd, Pokfulam, Hong Kong, China. Phone: 852 28192864; Fax: 852 28170859; Email: yuwanghk{at}hku.hk.

Adiponectin is an adipokine possessing growth inhibitory activities against various types of cancer cells. Our previous results demonstrated that adiponectin could impede Wnt/beta-catenin signalling pathways in MDA-MB-231 human breast carcinoma cells (Cancer Research, 2006; 66:11462-11470). Here, we extended our studies to elucidate the effects of adiponectin on regulating the expressions of Wnt inhibitory factor-1 (WIF1), a Wnt antagonist frequently silenced in human breast tumors. Our results showed that adiponectin time-dependently stimulated WIF1 gene and protein expressions in MDA-MB-231 cells. Over-expression of WIF1 exerted similar inhibitory effects to those of adiponectin on cell proliferations, nuclear beta-catenin activities, cyclin D1 expressions and serum-induced phosphorylations of Akt and glycogen synthase kinase-3beta. Blockage of WIF1 activities significantly attenuated the suppressive effects of adiponectin on MDA-MB-231 cell growth. Furthermore, our in vivo studies showed that both supplementation of recombinant adiponectin and adenovirus-mediated over-expression of this adipokine substantially enhanced WIF1 expressions in MDA-MB-231 tumors implanted in nude mice. More interestingly, we found that adiponectin could alleviate methylation of CpG islands located within the proximal promoter region of WIF1, possibly involving the specificity protein 1 (Sp1) transcription factor and its downstream target DNA methyltransferase 1 (DNMT1). Upon adiponectin treatment, the protein levels of both Sp1 and DNMT1 were significantly decreased. Using silencing RNA approaches, we confirmed that down-regulation of Sp1 resulted in an increased expression of WIF1 and decreased methylation of WIF1 promoter. Taken together, these data suggest that adiponectin might elicit its anti-tumor activities at least partially through promoting WIF1 expressions.

Key Words: Adiponectin • WIF1 • breast cancer • methylation • Sp1

* Co-first author

Received April 13, 2008; revised July 21, 2008; accepted August 8, 2008.


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