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

Victoria E. Villegas, Mohammed Ferdous Ur Rahman, Maite G. Fernandez-Barrena, Yumei Diao, Eleni Liapi, Enikö Sonkoly, Mona Ståhle, Andor Pivarcsi, Laura Annaratone, Anna Sapino, Sandra Ramírez Clavijo, Thomas R. Bürglin, Takashi Shimokawa, Saraswathi Ramachandran, Philipp Kapranov, Martin E. Fernandez-Zapico, Peter G. Zaphiropoulos

Resultado de la investigación: Contribución a RevistaArtículo

16 Citas (Scopus)

Resumen

Non-coding RNAs are a complex class of nucleic acids, with growing evidence supporting regulatory roles in gene expression. Here we identify a non-coding RNA located head-to-head with the gene encoding the Glioma-associated oncogene 1 (GLI1), a transcriptional effector of multiple cancer-associated signaling pathways. The expression of this three-exon GLI1 antisense (GLI1AS) RNA in cancer cells was concordant with GLI1 levels. siRNAs knockdown of GLI1AS up-regulated GLI1 and increased cellular proliferation and tumor growth in a xenograft model system. Conversely, GLI1AS overexpression decreased the levels of GLI1, its target genes PTCH1 and PTCH2, and cellular proliferation. Additionally, we demonstrate that GLI1 knockdown reduced GLI1AS, while GLI1 overexpression increased GLI1AS, supporting the role of GLI1AS as a target gene of the GLI1 transcription factor. Activation of TGFβ and Hedgehog signaling, two known regulators of GLI1 expression, conferred a concordant up-regulation of GLI1 and GLI1AS in cancer cells. Finally, analysis of the mechanism underlying the interplay between GLI1 and GLI1AS indicates that the non-coding RNA elicits a local alteration of chromatin structure by increasing the silencing mark H3K27me3 and decreasing the recruitment of RNA polymerase II to this locus. Taken together, the data demonstrate the existence of a novel non-coding RNA-based negative feedback loop controlling GLI1 levels, thus expanding the repertoire of mechanisms regulating the expression of this oncogenic transcription factor © 2014 Federation of European Biochemical Societies.
Idioma originalEnglish (US)
Páginas (desde-hasta)912-926
Número de páginas15
PublicaciónMolecular Oncology
Volumen8
N.º5
DOI
EstadoPublished - 2014

Huella dactilar

Untranslated RNA
Oncogenes
Glioma
Transcription Factors
Neoplasms
Cell Proliferation
Genes
Antisense RNA
RNA Polymerase II
Heterografts
Nucleic Acids
Chromatin
Exons
Up-Regulation

Citar esto

Villegas, Victoria E. ; Rahman, Mohammed Ferdous Ur ; Fernandez-Barrena, Maite G. ; Diao, Yumei ; Liapi, Eleni ; Sonkoly, Enikö ; Ståhle, Mona ; Pivarcsi, Andor ; Annaratone, Laura ; Sapino, Anna ; Ramírez Clavijo, Sandra ; Bürglin, Thomas R. ; Shimokawa, Takashi ; Ramachandran, Saraswathi ; Kapranov, Philipp ; Fernandez-Zapico, Martin E. ; Zaphiropoulos, Peter G. / Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1. En: Molecular Oncology. 2014 ; Vol. 8, N.º 5. pp. 912-926.
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title = "Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1",
abstract = "Non-coding RNAs are a complex class of nucleic acids, with growing evidence supporting regulatory roles in gene expression. Here we identify a non-coding RNA located head-to-head with the gene encoding the Glioma-associated oncogene 1 (GLI1), a transcriptional effector of multiple cancer-associated signaling pathways. The expression of this three-exon GLI1 antisense (GLI1AS) RNA in cancer cells was concordant with GLI1 levels. siRNAs knockdown of GLI1AS up-regulated GLI1 and increased cellular proliferation and tumor growth in a xenograft model system. Conversely, GLI1AS overexpression decreased the levels of GLI1, its target genes PTCH1 and PTCH2, and cellular proliferation. Additionally, we demonstrate that GLI1 knockdown reduced GLI1AS, while GLI1 overexpression increased GLI1AS, supporting the role of GLI1AS as a target gene of the GLI1 transcription factor. Activation of TGFβ and Hedgehog signaling, two known regulators of GLI1 expression, conferred a concordant up-regulation of GLI1 and GLI1AS in cancer cells. Finally, analysis of the mechanism underlying the interplay between GLI1 and GLI1AS indicates that the non-coding RNA elicits a local alteration of chromatin structure by increasing the silencing mark H3K27me3 and decreasing the recruitment of RNA polymerase II to this locus. Taken together, the data demonstrate the existence of a novel non-coding RNA-based negative feedback loop controlling GLI1 levels, thus expanding the repertoire of mechanisms regulating the expression of this oncogenic transcription factor {\circledC} 2014 Federation of European Biochemical Societies.",
author = "Villegas, {Victoria E.} and Rahman, {Mohammed Ferdous Ur} and Fernandez-Barrena, {Maite G.} and Yumei Diao and Eleni Liapi and Enik{\"o} Sonkoly and Mona St{\aa}hle and Andor Pivarcsi and Laura Annaratone and Anna Sapino and {Ram{\'i}rez Clavijo}, Sandra and B{\"u}rglin, {Thomas R.} and Takashi Shimokawa and Saraswathi Ramachandran and Philipp Kapranov and Fernandez-Zapico, {Martin E.} and Zaphiropoulos, {Peter G.}",
year = "2014",
doi = "10.1016/j.molonc.2014.03.009",
language = "English (US)",
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pages = "912--926",
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Villegas, VE, Rahman, MFU, Fernandez-Barrena, MG, Diao, Y, Liapi, E, Sonkoly, E, Ståhle, M, Pivarcsi, A, Annaratone, L, Sapino, A, Ramírez Clavijo, S, Bürglin, TR, Shimokawa, T, Ramachandran, S, Kapranov, P, Fernandez-Zapico, ME & Zaphiropoulos, PG 2014, 'Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1', Molecular Oncology, vol. 8, n.º 5, pp. 912-926. https://doi.org/10.1016/j.molonc.2014.03.009

Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1. / Villegas, Victoria E.; Rahman, Mohammed Ferdous Ur; Fernandez-Barrena, Maite G.; Diao, Yumei; Liapi, Eleni; Sonkoly, Enikö; Ståhle, Mona; Pivarcsi, Andor; Annaratone, Laura; Sapino, Anna; Ramírez Clavijo, Sandra; Bürglin, Thomas R.; Shimokawa, Takashi; Ramachandran, Saraswathi; Kapranov, Philipp; Fernandez-Zapico, Martin E.; Zaphiropoulos, Peter G.

En: Molecular Oncology, Vol. 8, N.º 5, 2014, p. 912-926.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1

AU - Villegas, Victoria E.

AU - Rahman, Mohammed Ferdous Ur

AU - Fernandez-Barrena, Maite G.

AU - Diao, Yumei

AU - Liapi, Eleni

AU - Sonkoly, Enikö

AU - Ståhle, Mona

AU - Pivarcsi, Andor

AU - Annaratone, Laura

AU - Sapino, Anna

AU - Ramírez Clavijo, Sandra

AU - Bürglin, Thomas R.

AU - Shimokawa, Takashi

AU - Ramachandran, Saraswathi

AU - Kapranov, Philipp

AU - Fernandez-Zapico, Martin E.

AU - Zaphiropoulos, Peter G.

PY - 2014

Y1 - 2014

N2 - Non-coding RNAs are a complex class of nucleic acids, with growing evidence supporting regulatory roles in gene expression. Here we identify a non-coding RNA located head-to-head with the gene encoding the Glioma-associated oncogene 1 (GLI1), a transcriptional effector of multiple cancer-associated signaling pathways. The expression of this three-exon GLI1 antisense (GLI1AS) RNA in cancer cells was concordant with GLI1 levels. siRNAs knockdown of GLI1AS up-regulated GLI1 and increased cellular proliferation and tumor growth in a xenograft model system. Conversely, GLI1AS overexpression decreased the levels of GLI1, its target genes PTCH1 and PTCH2, and cellular proliferation. Additionally, we demonstrate that GLI1 knockdown reduced GLI1AS, while GLI1 overexpression increased GLI1AS, supporting the role of GLI1AS as a target gene of the GLI1 transcription factor. Activation of TGFβ and Hedgehog signaling, two known regulators of GLI1 expression, conferred a concordant up-regulation of GLI1 and GLI1AS in cancer cells. Finally, analysis of the mechanism underlying the interplay between GLI1 and GLI1AS indicates that the non-coding RNA elicits a local alteration of chromatin structure by increasing the silencing mark H3K27me3 and decreasing the recruitment of RNA polymerase II to this locus. Taken together, the data demonstrate the existence of a novel non-coding RNA-based negative feedback loop controlling GLI1 levels, thus expanding the repertoire of mechanisms regulating the expression of this oncogenic transcription factor © 2014 Federation of European Biochemical Societies.

AB - Non-coding RNAs are a complex class of nucleic acids, with growing evidence supporting regulatory roles in gene expression. Here we identify a non-coding RNA located head-to-head with the gene encoding the Glioma-associated oncogene 1 (GLI1), a transcriptional effector of multiple cancer-associated signaling pathways. The expression of this three-exon GLI1 antisense (GLI1AS) RNA in cancer cells was concordant with GLI1 levels. siRNAs knockdown of GLI1AS up-regulated GLI1 and increased cellular proliferation and tumor growth in a xenograft model system. Conversely, GLI1AS overexpression decreased the levels of GLI1, its target genes PTCH1 and PTCH2, and cellular proliferation. Additionally, we demonstrate that GLI1 knockdown reduced GLI1AS, while GLI1 overexpression increased GLI1AS, supporting the role of GLI1AS as a target gene of the GLI1 transcription factor. Activation of TGFβ and Hedgehog signaling, two known regulators of GLI1 expression, conferred a concordant up-regulation of GLI1 and GLI1AS in cancer cells. Finally, analysis of the mechanism underlying the interplay between GLI1 and GLI1AS indicates that the non-coding RNA elicits a local alteration of chromatin structure by increasing the silencing mark H3K27me3 and decreasing the recruitment of RNA polymerase II to this locus. Taken together, the data demonstrate the existence of a novel non-coding RNA-based negative feedback loop controlling GLI1 levels, thus expanding the repertoire of mechanisms regulating the expression of this oncogenic transcription factor © 2014 Federation of European Biochemical Societies.

U2 - 10.1016/j.molonc.2014.03.009

DO - 10.1016/j.molonc.2014.03.009

M3 - Article

C2 - 24726458

VL - 8

SP - 912

EP - 926

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 5

ER -