SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas.

Currently available SMO targeted therapies in patients with basal cell nevus syndrome (BCNS) are associated with substantial tumor recurrence and clinical resistance. Strategies bypassing SMO and/or identifying additional downstream components of the Hedgehog (Hh) pathway could provide novel anti-tumor targets with a better therapeutic index. SOX9 is a Hh/GLI-regulated transcription factor known to be overexpressed in BCCs. A sequence motif search for SOX9-responsive elements identified three motifs in the promoter region of mTOR. In murine BCC cells, SOX9 occupies the mTOR promoter and induces its transcriptional activity. shRNA-mediated knockdown of SOX9, as well as SMO inhibition by itraconazole and vismodegib, reduces mTOR expression and the phosphorylation of known downstream mTOR targets. These effects culminate in diminishing the proliferative capacity of BCC cells, demonstrating a direct mechanistic link between the Hh and mTOR pathways capable of driving BCC growth. Furthermore, rapamycin, a pharmacologic mTOR inhibitor, suppressed growth of UV-induced BCCs in Ptch1/SKH-1 mice, a model that closely mimics the accelerated BCC growth pattern of patients with BCNS. Our data demonstrate that Hh signaling converges on mTOR via SOX9, and highlight the SOX9-mTOR axis as a viable additional target downstream of SMO that could enhance tumor elimination in BCC patients.