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GSE141323: A Tissue-Specific Tankyrase Inhibitor Drives Key Developmental and Oncogenic Pathways

Bulk RNA sequencing

Tissue-specific regulation of WNT and YAP/TAZ signaling is critical for optimal organismal growth, development, and maintenance. Uncontrolled activity often leads to developmental abnormalities and aggressive cancers. Tankyrase (TNKS) is a poly-ADP-ribose polymerase (PARP) that controls both WNT and YAP/TAZ signaling. However, it is unclear how TNKS activity is regulated in a tissue and cell-type specific manner. Here, we identified the previously uncharacterized prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS inhibitor. Structural and biochemical studies revealed that mechanistically PAGE4 inhibits TNKS through hijacking TNKS substrate binding pockets leading to the stabilization of TNKS substrates. In vitro cell culture and in vivo zebrafish and transgenic mouse model studies showed that PAGE4 is a potent inhibitor of TNKS and WNT signaling. Interestingly, PAGE4 is physiologically restricted to expression in select tissues and cell types, including WNT producing prostatic fibroblasts where spatiotemporal regulation of WNT signaling is critical for proper organ development. Surprisingly, PAGE4 is aberrantly expressed in hepatocellular carcinomas that bypass TNKS through mutant CTNNB1 driven WNT signaling. In vitro and in vivo tumorigenic studies revealed that PAGE4 initially function as a tumor suppressor through inhibition of WNT signaling, but upon CTNNB1 mutation becomes an oncogenic driver through YAP/TAZ signaling. Thus, we establish PAGE4 as a robust tissue-specific TNKS inhibitor that physiologically coordinates developmental WNT signaling, but genetic aberration during cancer progression re-wire PAGE4 into pro-oncogenic YAP/TAZ pathway. SOURCE: David Finkelstein ( - St Jude Children's Research Hospital

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