Cholesterol and its derivatives in Sonic Hedgehog signaling and cancer

The connection between the Hedgehog (HH) pathway and cholesterol has been recognized since the early days that shaped our current understanding of this unique pathway. Cholesterol and related lipids are intricately linked to HH signaling: from the role of cholesterol in HH biosynthesis to the modulation of HH signal reception and transduction by other sterols, passing by the phylogenetic relationships among many components of the HH pathway that resemble or contain lipid-binding domains. Here I review the connections between HH signaling, cholesterol and its derivatives and analyze the potential implications for HH-dependent cancers.

177Highlights► Cholesterol-modified Hedgehogs act on distant target cells as multimers or bound to lipoproteins. ► Activation of HH signaling is involved in development and maintenance of several cancer types. ► Intracellular cholesterol is required in the receiving cell for HH signal transduction. ► Two sterol types, oxysterols and vitamin D3 are agonists and inhibitors of SMO, respectively. ► Modulation of sterol synthesis could aid specific HH pathway inhibitors in the treatment of cancer.