A novel promoter-associated non-coding small RNA paGLI1 recruits FUS/P65 to transactivate GLI1 gene expression and promotes infiltrating glioma progression.

Abstract

Glioma-associated oncogene homolog 1 (GLI1) is a core component of the Hedgehog (HH) signalling pathway and is a transcription activator of numerous oncogenes, such as SOX9, VEGFA, BCL2, and CDK2. The complex regulation of GLI1 involves numerous pathways and molecules, including HH-dependent and independent, epigenetic and post-transcriptional mechanisms. Here, we report the discovery, characterization and function of a novel sense promoter-associated ncRNA, paGLI1 that is overexpressed in infiltrating glioma. We show that paGLI1 promotes GLI1 gene transcription through binding to and recruitment of the transcription factor complex FUS/P65 by interacting with paGLI1 DNA sequence. This interaction facilitates FUS/P65 binding to the GLI1 promoter to activate GLI1 transcription and hence its downstream oncogenes, which results in enhancement of glioma cell proliferation and invasiveness. Importantly, over-expression of paGLI1 is a significant unfavorable prognosticator for both disease-specific and progression-free survival in glioma patients, with relative risks being 2.932 (95% confidence interval: 1.280 to 6.713) (P < 0.05) and 2.284 (95% confidence interval: 1.051 to 4.966) (P < 0.05), respectively. The novel paGLI1/FUS/P65 regulatory mechanisms play important roles in infiltrating glioma progression and may serve as potential targets for future therapeutics.

• Authors: Jinjing Zhong, Miao Xu, Zhengzheng Su, Mengni Zhang, Tianping Yu, Ling Nie, Jing Gong, Xueqin Chen, Ni Chen, Qiao Zhou
• Journal: Cancer letters (Cancer Lett) Vol. 530 Pg. 68-84 (04 01 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 35051534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• FUS protein, human
• GLI1 protein, human
• RNA, Untranslated
• RNA-Binding Protein FUS
• Transcription Factor RelA
• Zinc Finger Protein GLI1

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Child
• Child, Preschool
• Female
• Gene Expression (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Glioma (genetics)
• Humans
• Infant
• Male
• Middle Aged
• Oncogenes (genetics)
• PC-3 Cells
• Promoter Regions, Genetic (genetics)
• RNA, Untranslated (genetics)
• RNA-Binding Protein FUS (genetics)
• Signal Transduction (genetics)
• Transcription Factor RelA (genetics)
• Young Adult
• Zinc Finger Protein GLI1 (genetics)