Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals

Abstract

A surprisingly large and unrelated number of human tumors depend on sustained HEDGEHOG-GLI (HH-GLI) signaling for growth. This includes cancers of the skin, brain, colon, lungs, prostate, blood and pancreas among others. The basis of such commonality is not obvious. HH-GLI signaling has also been shown to be active in and required for cancer stem cell survival and expansion in different cancer types, and its activity is essential not only for tumor growth but also for recurrence and metastatic growth, two key medical problems. Here we review recent data on the role of HH-GLI signaling in cancer focusing on the role of the GLI code, the regulated combinatorial and cooperative function of repressive and activating forms of all Gli transcription factors, as a signaling nexus that integrates not only HH signals but also those of multiple tumor suppressors and oncogenes. Recent data support the view that the context-dependent regulation of the GLI code by oncogenes and tumor suppressors constitutes a basis for the widespread involvement of GLI1 in human cancers, representing a perversion of its normal role in the control of stem cell lineages during normal development and homeostasis.

Figure 1

The GLI code. Different combinations of GLI activator (in green) and repressor forms (in red), with different potencies, are proposed to activate different sets of target genes that result in specific cellular fates and proliferation rates. The diagram illustrates how different (combinatorial and quantitative) GLI codes give different cellular outcomes.

Figure 2

Integration of oncogenic and tumor suppressor inputs by the GLI code in cancer. Upon inhibition of PTCH1 function by HH ligands, the repression on SMOH is released, SMOH moves into the primary cilium and activates downstream signaling by stabilizing activating full-length GLI proteins (GLI1) and blocking the production of GLI repressors (GLI3R). The mammalian GLI code includes three proteins. Generally, GLI1 is an activator although it exists in N′ and C′ Δ deleted activator and repressor forms, respectively, GLI2 has activator and C′ Δ repressor functions and GLI3 is a weak activator and its C′ Δ form is a strong repressor. Components of the classical HH pathway are in filled circles, in red for inhibitors and in green for activators. Positive and negative regulators of HH-GLI signaling are in unfilled circles, in blue for the PGF-RTK-RAS-RAF-MEK, PI3K-AKT and JUN pathways, in green for activators and in red for repressors. The color of the arrow is dictated by the final effect on the GLI code: red arrow for a final repressive effect, green arrow for a final activating effect on the GLI code. See text for further details.

Figure 3

Regulation of the GLI code by oncogenic and tumor suppressor inputs in stem cells and cancer. During development, HH signaling tightly promotes the formation of labile GLI activators. The action of tumor suppressors further restrains GLI positive function, which is boosted by converging pathways and inputs such as those triggered by oncogenic PGF-RTK signals. (A and B) Mutations or epigenetic changes that lead to the loss of tumor suppressors (for example p53, PTEN) and activation of oncogenic pathways (for example RAS-RAF-MEK, PI3K-AKT) could unlock the normally restricted proliferative and self-renewing activities of GLI activators leading to an abnormal expansion of cancer stem cells (Ruiz i Altaba et al., 2007).