Dynamic S-palmitoylation of glioma-associated oncogene 1 regulates the incidence and progression of Sonic Hedgehog medulloblastoma

Abstract Aberrant activation of the Sonic Hedgehog (SHH)-glioma-associated oncogene 1 (GLI1) signaling pathway is a determinant driver of basal cell carcinoma (BCC) and SHH-subgroup medulloblastoma (MB SHH ). Here, we demonstrate the role of S-palmitoylation and depalmitoylation of GLI1 in the regulation of incidence and progression of MB SHH . High expression of acyltransferase ZDHHC13 in MB SHH induces S-palmitoylation of human GLI1 at Cys1034, stabilizes GLI1 by preventing its ubiquitin-dependent proteasomal degradation, and in turn activates this signaling pathway to promote the progression of MB SHH . Conversely, the deacylase ABHD17A depalmitoylates GLI1 at Cys1034, destabilizes GLI1, and in turn inactivates this signaling pathway. As a result, conditional knockout of Zdhhc13 in cerebellar granule neuron precursors (GNPs) significantly alleviates the severity of MB SHH induced by constitutively active Smoothened ( Smo-M2 ) overexpression and markedly extends overall survival, whereas knockout of Abhd17a increases the incidence of MB SHH induced by Patched-1 ablation, rather than its progression. Together, these findings uncover the dynamic regulation of GLI1 palmitoylation and depalmitoylation by the ZDHHC13 and ABHD17A and subsequent GLI1 stabilization and destabilization as a hitherto uncharacterized mechanism controlling SHH/GLI1 signaling and may provide additional targets for therapeutic intervention of MB SHH .