Identification of novel non‐coding RNA‐based negative feedback regulating the expression of the oncogenic transcription factor GLI1

Villegas, Victoria Eugenia; Rahman, Mohammed Ferdous‐Ur; Fernández‐Barrena, Maite G.; Diao, Yutao; Liapi, Eleni; Sonkoly, Enikö; Ståhle, Mona; Pivarcsi, Andor; Annaratone, Laura; Sapino, Anna; Ramírez-Clavijo, Sandra; Bürglin, Thomas R.; Shimokawa, Tetsuya; Saraswathi, R.; Kapranov, Philipp; Fernández-Zapico, Martín E.; Zaphiropoulos, Peter G.

doi:10.1016/j.molonc.2014.03.009

Cited by 25 publications

(27 citation statements)

References 44 publications

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“…In line with its impact on GLI1 expression, FOXS1 knockdown increased the proliferation of both Rh36 and Daoy cells, and this contrasts the decreased proliferation elicited by GLI1 knockdown (Fig. A,B) (Villegas et al ., ). Similar changes in proliferation were also observed with the human embryonic palatal mesenchyme (HEPM) cell line (Fig.…”

Section: Resultsmentioning

confidence: 97%

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

et al. 2018

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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.

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Section: Resultsmentioning

confidence: 97%

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

et al. 2018

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“…Genetic and pharmacologic inhibition of Gli1/2 have been successful in reducing fibrosis after either UUO or I/R, though there is some evidence that other pathways (e.g. TGF-β) may also regulate this protein(40, 42–44). Thus the hedgehog pathway likely mediates epithelial/fibroblast crosstalk, however the mechanisms whereby it promotes TIF after renal injury requires further investigation.…”

Section: Epithelial/epithelial and Epithelial/fibroblast Crosstalkmentioning

confidence: 99%

Progression of chronic kidney disease: too much cellular talk causes damage

Gewin

Zent

Pozzi

2017

Kidney International

115

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Tubulointerstitial fibrosis, tubular atrophy and peritubular capillary rarefaction are major hallmarks of chronic kidney disease. The tubulointerstitium consists of multiple cell components including tubular epithelia, mesenchymal (fibroblasts and pericytes), endothelial, and inflammatory cells. Crosstalk among these cell components is a key component in the pathogenesis of this complex disease. Following severe or recurrent injury, the renal tubular epithelial cells undergo changes in structure and cell cycle which are accompanied by altered expression and productions of cytokines. These cytokines contribute to the initiation of the fibrotic response by favoring activation of fibroblasts, recruitment of inflammatory cells, and loss of endothelial cells. This review focuses on how augmented growth factor and cytokine production induces epithelial crosstalk with cells in the interstitium to promote progressive tubulointerstitial fibrosis after renal injury.

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“…Menin recruits PRMT5 to the GLI1 promoter to lay down the H4R3me2 repressive mark in a Hedgehog signalingindependent manner 42 and a recently identified noncoding RNA induces H3K27me3 at the GLI1 promoter, thereby reducing RNA polymerase II recruitment. 43 GLI1 has frequently been implicated in cancer cell therapy resistance through decreased chemotherapy and radiotherapy responsiveness [44][45][46][47][48] and increased expression of cell surface drug transporters. [49][50][51] Recently, GLI1 was shown to drive resistance of AML cells to ribavirin and cytarabine through UGT1A-dependent glucuronidation of the compounds and inhibition of GLI1 with GANT61 restored sensitivity.…”

Section: Discussionmentioning

confidence: 99%

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

et al. 2016

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Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostatresistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 smallmolecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

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Identification of novel non‐coding RNA‐based negative feedback regulating the expression of the oncogenic transcription factor GLI1

Cited by 25 publications

References 44 publications

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

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

Progression of chronic kidney disease: too much cellular talk causes damage

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

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