Cholesterol and its derivatives in Sonic Hedgehog signaling and cancer

Abstract

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.

Figure 1

Overview of the HH signaling network. HH signaling is initiated upon binding of a HH protein to its receptor PTC, which de-represses SMO. In the canonical pathway, SMO activation leads to increased transcriptional activity of the GLI family of transcription factors. GLI-independent actions of PTC and SMO are collectively known as “non-canonical” signaling.

Figure 2

Summary of association of genetic alterations of the HH pathway and cancer type. In the case of SHH and IHH is by overexpression without any reported mutations, for PTC1 and SU(FU) the defect is deficiency or loss-of-function mutations, for SMO is gain-of-function mutations and for GLI is gene amplification.

Figure 3

Role of cholesterol and its derivatives in the HH pathway. Arrows indicate positive interactions, stopped lines indicate inhibition of the component.