Sterol regulation of developmental and oncogenic Hedgehog signaling

The Hedgehog (Hh) family of lipid-modified signaling proteins directs embryonic tissue patterning and postembryonic tissue homeostasis, and dysregulated Hh signaling drives familial and sporadic cancers. Hh ligands bind to and inhibit the tumor suppressor Patched and allow the oncoprotein Smoothened (SMO) to accumulate in cilia, which in turn activates the GLI family of transcription factors. Recent work has demonstrated that endogenous cholesterol and oxidized cholesterol derivatives (oxysterols) bind and modulate SMO activity. Here we discuss the myriad sterols that activate or inhibit the Hh pathway, with emphasis on endogenous 24(S),25epoxycholesterol and 313,5a-dihydroxycholest-7-en-6-one, and propose models of sterol regulation of SMO. Synthetic inhibitors of SMO have long been the focus of drug development efforts. Here, we discuss the possible utility of steroidal SMO ligands or inhibitors of enzymes involved in sterol metabolism as cancer therapeutics.

Automated summary

This article discusses the role of the Hedgehog (Hh) family of lipid-modified signaling proteins in embryonic tissue patterning and postembryonic tissue homeostasis, as well as the involvement of dysregulated Hh signaling in familial and sporadic cancers. It also explores the binding and modulation of SMO activity by endogenous cholesterol and oxidized cholesterol derivatives. The article proposes models of sterol regulation of SMO and discusses the potential utility of steroidal SMO ligands or inhibitors of enzymes involved in sterol metabolism as cancer therapeutics.