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Identification of novel GLI1 target genes and regulatory circuits in human cancer cells.
- Source :
-
Molecular oncology [Mol Oncol] 2018 Oct; Vol. 12 (10), pp. 1718-1734. Date of Electronic Publication: 2018 Aug 30. - Publication Year :
- 2018
-
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.<br /> (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Subjects :
- Cell Line, Tumor
Cell Proliferation genetics
Forkhead Transcription Factors genetics
Forkhead Transcription Factors metabolism
Gene Expression Regulation, Neoplastic
HEK293 Cells
Hedgehog Proteins metabolism
Humans
Medulloblastoma genetics
Medulloblastoma pathology
RNA, Small Interfering metabolism
Reproducibility of Results
Rhabdomyosarcoma genetics
Rhabdomyosarcoma pathology
Gene Regulatory Networks
Neoplasms genetics
Zinc Finger Protein GLI1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 12
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 30098229
- Full Text :
- https://doi.org/10.1002/1878-0261.12366