Abstract 3062: Transcriptional repressor Kaiso promotes cancer progression by targeting miR-31 in prostate cancer.

Abstract

Abstract Metastatic spread of prostate cancer (PCa) is responsible for the majority of prostate cancer-related deaths. Whereas socioeconomic factors, different geographic areas and ethnicity contribute to the incidence and mortality rates of this disease, they cannot fully explain the tumor biology. Our understanding of the mechanisms that drive PCa progression and metastasis is still limited. Kaiso belongs to a BTB/POZ zinc finger protein family and is known as a transcriptional repressor by binding to sequence-specific Kaiso binding sites or methyl-CpG dinucleotide pairs. Kaiso expression and localization have been reported to correlate with the prognosis and metastatic potential in several human malignancies. Previous studies from our lab showed that the progression of PCa is closely associated with the over-expression and nuclear translocation of Kaiso. Our objective here is to explore the potential molecular mechanisms underlying Kaiso mediated increase in PCa progression. MicroRNAs play an emerging role in cancer initiation and progression. Therefore we proposed to investigate Kaiso targeting microRNAs and their roles in PCa. PC-3 cells, a highly metastatic PCa cell line, were stably transfected with a shRNA plasmid against human Kaiso or a scramble control. Two clones exhibited >80% downregulation of Kaiso in PC-3 cells at either the transcriptional or translational levels were used for further studies. We determined miRNA expression profiles correlated with Kaiso knock down and DNMT1 inhibitor 5-Aza de-methylation treatment using microRNA arrays. Comparative analysis revealed 11 miRNAs were significantly altered by Kaiso knock down and 32 miRNAs were significantly altered by 5-Aza treatment (> 2 fold, p<0.05). Real-time PCR confirmed that miR-31 expression was up-regulated in both Kaiso knock down cells and 5-Aza treated cells. From the analysis of differentially expressed miRNAs, miR-31 expression was also negatively correlated with kaiso expression in a set of prostate cell lines. ChIP assay revealed that kaiso directly binds to miR-31 promoter. The restoration of miR-31 suppressed cell proliferation; induced apoptosis and inhibited tumor cell invasion and metastasis in vitro. Inhibition of miR-31 in PC-3 shKaiso cells restored kaiso knock down-inhibited cell proliferation; migration and metastasis. Xenograft model indicated that miR-31 overexpression significant suppressed tumor formation in vivo. Taken together, our studies suggest that Kaiso regulates specific miRNA expression in PCa cells, indicating that Kaiso could promote cancer progression through regulating miR-31 expression in a methylation dependent manner. Citation Format: Honghe Wang, ShaNekkia Black, Wei Liu, Fu Zhao, Timothy Turner, Clayton Yates. Transcriptional repressor Kaiso promotes cancer progression by targeting miR-31 in prostate cancer. [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 3062. doi:10.1158/1538-7445.AM2013-3062 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.