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.
N1 - Funding Information:
This study was supported by the Swedish Childhood Cancer Foundation ( PROJ12/032 ), the Swedish Cancer Fund ( CAN 2009/579 ), the Swedish Research Council ( K2008-67X-20778-01-3 ) and the AFA Insurance ( Dnr: 130014 ). VEV, YD and EL were funded by scholarships from the ERACOL program of the European Union , the China Scholarship Council and the Erasmus Scholarship Program . MEFZ and MGFB were supported by National Cancer Institute CA165076 and Mayo Clinic Cancer Center .
PY - 2014/7
Y1 - 2014/7
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
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
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U2 - 10.1016/j.molonc.2014.03.009
DO - 10.1016/j.molonc.2014.03.009
M3 - Research Article
C2 - 24726458
AN - SCOPUS:84903511914
SN - 1574-7891
VL - 8
SP - 912
EP - 926
JO - Molecular Oncology
JF - Molecular Oncology
IS - 5
ER -
