Open AccessIdentification of novel GLI1 target genes and regulatory circuits in human cancer cells
Author(s) -
Diao Yumei,
Rahman Mohammed FerdousUr,
Vyatkin Yuri,
Azatyan Ani,
St. Laurent Georges,
Kapranov Philipp,
Zaphiropoulos Peter G.
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12366
Subject(s) - gli1 , biology , transcription factor , hedgehog , carcinogenesis , cancer research , sonic hedgehog , effector , medulloblastoma , signal transduction , cancer , gene , computational biology , genetics , microbiology and biotechnology
Hedgehog ( HH ) signaling is involved in many physiological processes, and pathway deregulation can result in a wide range of malignancies. Glioma‐associated oncogene 1 ( GLI 1) is a transcription factor and a terminal effector of the HH cascade. Despite its crucial role in tumorigenesis, our understanding of the GLI 1 cellular targets is quite limited. In this study, we identified multiple new GLI 1 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 GLI 1 can modulate effects on the targets. Furthermore, one of the top targets, FOXS 1 , 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 GLI 1 in medulloblastoma and rhabdomyosarcoma cells. Moreover, FOXS 1 is both highly expressed and positively correlated with GLI 1 in medulloblastoma samples of the Sonic HH subgroup, further arguing for the existence of FOXS 1/ GLI 1 interplay in human tumors. Consistently, high FOXS 1 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.