A Novel Mechanism for Activation of GLI1 by Nuclear SMO That Escapes Anti-SMO Inhibitors.

Small-molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients respond poorly. In this study, we report the results of investigations on PTCH1 signaling in the HH pathway that suggest why most patients with BCC respond poorly to SMO inhibitors. In immortalized human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, although siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacologic inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localization of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localization signal [N(o)LS]. Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistologic analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pattern was heterogeneous between tumors. In PTCH1-silenced cells, >80% of the genes found to be differentially expressed were unaffected by SMO inhibitors, including the putative BCC driver gene CXCL11. Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology and highlights a novel nuclear mechanism of SMO-GLI1 signaling that is unresponsive to SMO inhibitors.Significance: This study describes novel noncanonical Hedgehog signaling, where SMO enters the nucleus to activate GLI1, a mode that is unaffected by SMO inhibitors, thus prompting re-evaluation of current BCC treatment as well as new potential therapies targeting nuclear SMO. Cancer Res; 78(10); 2577-88. ©2018 AACR.The authors gratefully acknowledge the funding from the British Skin Foundation. The authors also thank Anna Saran (ENEA, Rome, Italy) for providing mouse BCC tissue for immunohistochemistry and Dr. Monika Cichon for the shRNA control sequences. The authors also thank the Dr. Hadwen Trust (DHT) for Humane Research for additional funding to develop human models for human disease and confirm that no funding from the DHT was used for any animal research in this article

Acne and Rosacea

Acne, one of the most common skin diseases, affects approximately 85% of the adolescent population, and occurs most prominently at skin sites with a high density of sebaceous glands such as the face, back, and chest. Although often considered a disease of teenagers, acne is occurring at an increasingly early age. Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia. Both acne and rosacea have a multifactorial pathology that is incompletely understood. Increased sebum production, keratinocyte hyper-proliferation, inflammation, and altered bacterial colonization with Propionibacterium acnes are considered to be the underlying disease mechanisms in acne, while the multifactorial pathology of rosacea is thought to involve both vasoactive and neurocutaneous mechanisms. Several advances have taken place in the past decade in the research field of acne and rosacea, encompassing pathogenesis and epidemiology, as well as the development of new therapeutic interventions. In this article, we provide an overview of current perspectives on the pathogenesis and treatment of acne and rosacea, including a summary of findings from recent landmark pathophysiology studies considered to have important implications for future clinical practice. The advancement of our knowledge of the different pathways and regulatory mechanisms underlying acne and rosacea is thought to lead to further advances in the therapeutic pipeline for both conditions, ultimately providing a greater array of treatments to address gaps in current management practices