Abstract 1794: Cross-regulation of polycomb group protein BMI1 and WNT inhibitors.

Abstract Polycomb group (PcG) proteins are evolutionarily conserved gene silencers, which determine cell fate decisions during development. These proteins are often aberrantly expressed in cancer cells. In particular, BMI1 and EZH2 are known to be overexpressed in a number of human malignancies including breast and prostate cancers. In vitro models of cancer development strongly support oncogenic role of overexpressed BMI1 in cancer and metastasis. BMI1 is known to be required for self-renewal of neural, hematopoietic, intestinal and mammary stem cells. In addition, BMI1 is downregulated in senescent cells, and this downregulation may contribute to age-related pathologies. BMI1 is also suspected to play a role in cancer stem cell development and increase stem cell-ness of tumors to promote drug resistance. Despite its role in cancer, stem cell phenotype, development and aging, very little is known about the signaling pathways that regulate the expression of BMI1. Here we report that BMI1 activates WNT pathway and upregulates its target genes such as Cyclin D1 and c-Myc. Using promoter-reporter assays, quantitative RT-PCR and Western blot analyses, we show that BMI1 auto-activates its expression via an E-box present in its promoter. Because auto-activation of BMI1 depends on E-box sequences present in its promoter, we hypothesized that BMI1 may regulate expression of c-Myc directly or indirectly via activation of WNT pathway. Indeed, our data suggest that BMI1 upregulated expression of c-Myc via activation of WNT pathway. Further dissection of this regulation revealed that BMI1 represses expression of WNT inhibitors, in particular DKK family of proteins such as DKK1, DKK2 and DKK3. Interestingly, we also found that DKK1 inhibits expression of BMI1, which also depends on E-box present in BMI1 promoter. Thus BMI1 and WNT inhibitors such as DKK1 cross-regulate each other's expression. We speculate that such regulation might favor BMI1 overexpression in cancer cells via increased WNT activity and c-Myc expression. On the other hand, increased expression of WNT inhibitors such as DKK1 might favor BMI1 downregulation in senescent and aged tissues. Thus, a fine tuned positive feedback loop controls BMI1 expression via WNT signaling pathway, and this feedback loop may be relevant to the role of BMI1 in cancer, stem cells and senescence. Citation Format: Joon-Ho Cho, Manjari Dimri, Goberdhan P. Dimri. Cross-regulation of polycomb group protein BMI1 and WNT inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1794. doi:10.1158/1538-7445.AM2013-1794