Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

Abstract

Hedgehog (HH) signaling is involved in many physiological processes, and pathway deregulation can result in a wide range of malignancies. Glioma‐associated oncogene 1 (GLI1) is a transcription factor and a terminal effector of the HH cascade. Despite its crucial role in tumorigenesis, our understanding of the GLI1 cellular targets is quite limited. In this study, we identified multiple new GLI1 target genes using a combination of different genomic surveys and then subjected them to in‐depth validation in human cancer cell lines. We were able to validate >90% of the new targets, which were enriched in functions involved in neurogenesis and regulation of transcription, in at least one type of follow‐up experiment. Strikingly, we found that RNA editing of GLI1 can modulate effects on the targets. Furthermore, one of the top targets, FOXS1, a gene encoding a transcription factor previously implicated in nervous system development, was shown to act in a negative feedback loop limiting the cellular effects of GLI1 in medulloblastoma and rhabdomyosarcoma cells. Moreover, FOXS1 is both highly expressed and positively correlated with GLI1 in medulloblastoma samples of the Sonic HH subgroup, further arguing for the existence of FOXS1/GLI1 interplay in human tumors. Consistently, high FOXS1 expression predicts longer relapse‐free survival in breast cancer. Overall, our findings open multiple new avenues in HH signaling pathway research and have potential for translational implications.

FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer

“…recently published that both GLI1 and FOXS1 are highly expressed and positively correlated with GLI1 in medulloblastoma samples 15 , further suggesting that the existence of FOXS1/GLI1 interplay in human cancers may not be dependent on the type of human tumor. Interestingly, FOXS1 expression can reduce GLI1 transcriptional activity, and GLI1/FOXS1 exhibit direct protein–protein interaction in HEK293A cells 15,37 . In our study, we found that GLI1 inhibited FOXS1 expression by binding the promoter regions of FOXS1, suggesting that GLI1 and FOXS1, two oncogenes, may combine and suppress each other’s expression.…”

“…Yumei Diao et al . recently reported that FOXS1 was one of the top targets of the GLI1 gene and was shown to act in a negative feedback loop limiting the cellular effects of GLI1 in medulloblastoma and rhabdomyosarcoma cells 15 . However, the interplay of GLI1 and FOXS1 in GC cells has not been reported.…”

Primary myxoid and epithelioid mesenchymal tumor of the kidney with a novel GLI1‐FOXO4 fusion

“…GLI1 has a transcriptional activator function with a well‐established role in the Hedgehog signaling pathway, for which deregulation has been implicated in the pathogenesis of numerous malignancies 18 . GLI1 rearrangements have been identified in several malignant soft tissue tumors including pericytoma‐like tumors, 19,20 gastric plexiform fibromyxoma, 21 gastroblastoma, 22 and a group of malignant epithelioid neoplasms with frequent S100 protein expression.…”

Circular RNA DGKB Promotes the Progression of Neuroblastoma by Targeting miR-873/GLI1 Axis

“…It's well-known that Hedgehog (HH) signaling pathway plays critical roles in amount of cancers, including NB ( 43 – 46 ). GLI1, a terminal effectors of the HH factors, was reported to serve as an oncogene in wide ranges of cancers, such as breast cancer ( 47 ), CRC ( 48 ), prostate cancer ( 49 ), glioma ( 50 ), pancreatic cancer ( 51 ), gastric cancer ( 52 ), and cervical cancer ( 53 ).…”