Phospholipase D1 drives a positive feedback loop to reinforce the Wnt/beta-catenin/TCF signaling axis.

Activation of the Wnt signaling pathway occurs frequently in human cancers, but an understanding of the targets and regulation of this important pathway remains incomplete. In this study, we report that phospholipase D (PLD), a cell survival mediator that is upregulated in cancer, is an important target of the Wnt signaling pathway that functions in a positive feedback loop to reinforce pathway output. PLD1 expression and activity was enhanced by treatment with Wnt3a and glycogen synthase kinase-3 inhibitors, and the Wnt pathway-regulated transcription factors beta-catenin and TCF-4 were required for this effect. Three functional TCF-4-binding sites were identified within the PLD1 promoter. Interestingly, suppressing PLD1 blocked the ability of beta-catenin to transcriptionally activate PLD1 and other Wnt target genes by preventing beta-catenin/TCF-4 complex formation. Conversely, tactics to elevate intracellular levels of phosphatidic acid, the product of PLD1 enzyme activity, enhanced beta-catenin/TCF-4 complex formation as well as beta-catenin-dependent TCF transcriptional activity. In cell-based assays, PLD1 was necessary for the anchorage-independent growth driven by Wnt/beta-catenin signaling, whereas beta-catenin/TCF-4 was necessary for the anchorage-independent growth driven by PLD1 activation. Taken together, our findings define a function for PLD1 in a positive feedback loop of Wnt/beta-catenin/TCF-4 signaling that provides new mechanistic insights into cancer, with implications of novel strategies to disrupt Wnt signaling in cancer.

Kang DW ，Lee SH ，Yoon JW ，Park WS ，Choi KY ，Min do S ... -  《-》

Positive feedback regulation between phospholipase D and Wnt signaling promotes Wnt-driven anchorage-independent growth of colorectal cancer cells.

Kang DW ，Min do S 《PLoS One》

Redundant expression of canonical Wnt ligands in human breast cancer cell lines.

Benhaj K ，Akcali KC ，Ozturk M 《ONCOLOGY REPORTS》

Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway.

Shan BE ，Wang MX ，Li RQ 《-》

The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes beta-catenin/TCF-mediated transcription.

Navarro D ，Agra N ，Pestaña A ，Alonso J ，González-Sancho JM ... -  《-》