The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH,
protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely
glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of GLIs must be tightly regulated as they modulate target genes which control tissue patterning, stem cell maintenance, and differentiation during development. However, dysregulation or mutations in HH signaling leads to
genomic instability (GI) and various
cancers, for example, germline mutation in PTCH1 lead to
Gorlin syndrome, a condition where patients develop numerous
basal cell carcinomas and rarely
rhabdomyosarcoma (RMS). Activating mutations in SMO have also been recognized in sporadic cases of
medulloblastoma and SMO is overexpressed in many other
cancers. Recently, studies in several human
cancers have shown that GLI1 expression is independent from HH
ligand and canonical intracellular signaling through PTCH and SMO. In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat
sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC),
transforming growth factor β (TGFβ), wingless-type MMTV integration site family (WNT) and β-
catenin. Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact
tumor response to chemo- and
radiation therapies. Furthermore, the ineffectiveness of SMO inhibitors in clinical studies argues for the development of GLI1-specific inhibitors in order to develop effective therapeutic modalities to treat these
tumors. In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses,
carcinogenesis and chemoresistance.