Title: A non-canonical Hippo signaling pathway regulates DeltaNp63 in cancer cells
Description: The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cancers, while its expression is often repressed in breast cancers. In the canonical conserved Hippo pathway, known to play a complex role in regulating the growth of cancer cells, the protein kinases Mammalian Ste20 like kinases 1/2 (MST) and Large tumor suppressor kinases 1/2 (LATS) act sequentially to phosphorylate and inhibit the Yes-associated Protein/Transcriptional coactivator PDZ binding transcription factors (YAP/TAZ). We found that in the MCF10A mammary epithelial cell line and insquamous and breast cancer cell lines, expression of deltaNp63 RNA and protein is strongly repressed by inhibition of specific components of the Hippo pathway in a manner that is independent of p53. While the Hippo pathway protein kinases MST1/2 and LATS1 are required for p63 expression, the next step of the pathway namely phosphorylation and degradation of the YAP/TAZ transcriptional activators, is not required for repression of p63.

This suggests that regulation of p63 expression occurs by a non-canonical version of the Hippo pathway. Interestingly, we observed that experimentally lowering p63 expression leads to increased Yes Associated Protein protein levels, thereby constituting a feedback loop. In addition, p63 loss reduces the growth of MCF10A and squamous cancer cell lines. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells.