Genome-Wide RNAi Screen Reveals Disease-Associated Genes That Are Common to Hedgehog and Wnt Signaling

Loss of the kinase and tumor suppressor Stk11 (Lkb1) has opposite effects on Hh and Wnt signaling. Yin and Yang of Stk11 A screen to link positive regulators of the Hedgehog (Hh) pathway with human disease revealed a protein that sets the threshold of Hh and Wnt signaling, two pathways involved in embryonic development and adult tissue regeneration, as well as pathological conditions, such as cancer. The tumor suppressor Stk11 (also known as Lkb1) is a kinase that has been implicated in establishing cell polarity. Jacob et al. found that Stk11 was required for the formation of full-length primary cilia, to limit production of the Gli repressor, and thereby enhanced Hh signaling. In contrast, Stk11 restricted the availability of Disheveled, limiting Wnt signaling. Thus, the absence of Stk11 resulted in a higher threshold for Hh signaling but a lower threshold for Wnt signaling. The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.

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