Transcriptional repressor Kaiso promotes epithelial to mesenchymal transition and metastasis in prostate cancer through direct regulation of miR-200c

Abstract

The loss of miR-200 family, through DNA methylation, results in cancer cells undergoing an epithelial to mesenchymal transition (EMT), and metastasis. In this study, we established that the transcriptional repressor Kaiso directly binds methylated regions of the miR-200 family, and this is reversed with 5-aza treatment. sh-Kaiso PC-3 cells display increased miR-200-a/b/c, miR-141, and miR-429 expression, with miR-200c demonstrating the most significant increase. Interestingly, overexpression of EGFR or treatment with EGF decreases miR-200c expression and this is reversed after treatment with EGFR specific kinase inhibitor PD153035. However, EGF did not have a significant effect on miR-200c in sh-Kaiso DU-145 or PC-3 cell lines, suggesting Kaiso silences miR-200c through the activation of EGFR signaling. Overexpression of Kaiso in LNCaP cells results in decreased expression of miR-200-a/b/c, miR-141, and miR-429, along with increased expression of ZEB1, p-EGFR and total EGFR levels. Overexpression of miR200c in PC-3 cells results in decreased expression of EGFR, ZEB1, ERK1/2 and Kaiso. Additionally, sh-Kaiso PC-3 demonstrates reduced in vivo tumor formation and metastasis. Thus, our data suggests that EGFR signaling regulates the silencing of miR-200 family through Kaiso binding to methylated regions in the promoter.

Dancing from bottoms up – Roles of the POZ-ZF transcription factor Kaiso in Cancer

“…Similar to findings in breast tumor cell lines, Kaiso depletion inhibited the proliferation of a glioma cell line accompanied by reduced expression of cell cycle regulators PCNA, CDK2, CDK4, Cyclin D1 and Cyclin E1 and increased expression of p21 and p27. Reduced expression of mesenchymal markers (Vimentin, N-cadherin) and increased expression of epithelial markers (E-cadherin) was also observed upon depletion of Kaiso in glioma cells [92], similar to what has been reported in both breast and prostate cancer cells [19, 83]. In addition to reinforcing Kaiso’s role as a regulator of EMT, these studies have also identified the miR-181 family as novel regulators of Kaiso expression.…”

“…PCa patients with Kaiso high and miR-31 low tumors had worse overall survival relative to patients with only Kaiso high tumors or miR-31 low tumors, suggesting that Kaiso promotes poor PCa survival via regulation of miR-31 expression. Most recently, Kaiso was also implicated in regulating the miR-200 family that suppresses EMT in PCa cells [19]. Upon Kaiso depletion in selected PCa cells, there was a significant increase of these miRNAs—similar to what was observed upon demethylation—and a decrease in downstream EMT targets such as ZEB1/2, Twist and Snail.…”

“…Upon Kaiso depletion in selected PCa cells, there was a significant increase of these miRNAs—similar to what was observed upon demethylation—and a decrease in downstream EMT targets such as ZEB1/2, Twist and Snail. Furthermore, using an in vivo mouse xenograft model, Kaiso-depleted PC3 cells subcutaneously injected into mice exhibited decreased tumor growth and less metastases compared to mice injected with control PC3 cells [19]. Collectively, these data further highlight Kaiso’s role in EMT and PCa tumor metastasis.…”

“…Indeed, most studies to date have reported on Kaiso’s transcriptional repression of target genes including E-cadherin [13, 14], Wnt 11 [4], matrilysin [15], HIF1A [16], CDKN2A [17], miR-31 [18] and the miR-200 family [19]. While fewer studies have reported on Kaiso-mediated transcriptional activation of target genes [20, 21], recent studies suggest that transcriptional activation may be Kaiso’s preferred mode of transcriptional regulation.…”

Diversity in the Era of Precision Medicine - From Bench to Bedside Implementation

“…24 Kaiso promotes cancer metastases through direct regulation of epithelial-mesenchymal transition (EMT) genes and several other tumor-suppressor micro RNAs. 25 In breast cancer, overexpression of Kaiso in infiltrating ductal carcinomas (IDCs) was associated with loss of E-cadherin and increased cell migration and invasiveness. Depletion of Kaiso resulted in increased cell adhesion and development of small-sized primary tumors in in vivo and in vitro studies.…”