Hedgehog signaling in colorectal cancer: a spiny issue gets smoothened

The Hh pathway has been recognized as one of the major regulators of cell growth and differentiation during embryogenesis and early development of vertebrates (1). Generally, it is inactivated in adults but reactivation via inappropriate mutation or deregulation of this pathway may play a crucial role in tumor development. Activation of canonical Hh signaling occurs when one of the ligands, i.e., Sonic (Shh), Desert (Dhh) or Indian (Ihh) Hedgehog binds to its receptor Patched 1 (PTCH1). This relieves the repression of Smoothened (SMO) by PTCH1, thereby initiating a signaling cascade that leads to the activation of the Glioma-associated oncogene (GLI) transcription factors, which will translocate to the nucleus and promote transcription of the Hh target genes.