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

• Published in: Cancer letters 2022-04, Vol.530, p.68-84
• Main Authors: Zhong, Jinjing, Xu, Miao, Su, Zhengzheng, Zhang, Mengni, Yu, Tianping, Nie, Ling, Gong, Jing, Chen, Xueqin, Chen, Ni, Zhou, Qiao
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Biotechnology; Brain cancer; Brain tumor; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Child; Child, Preschool; Cyclin-dependent kinases; Epigenetics; Female; Gene expression; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - genetics; GLI1 gene; Glioma; Glioma - genetics; Glioma cells; Hedgehog protein; Hedgehog signalling pathway; Humans; Infant; Invasiveness; Kinases; Laboratories; Male; Medical prognosis; Middle Aged; Nucleotide sequence; Oncogenes - genetics; Overexpression; PC-3 Cells; Post-transcription; Promoter Regions, Genetic - genetics; Risk assessment; RNA, Untranslated - genetics; RNA-Binding Protein FUS - genetics; Short RNA; Signal transduction; Signal Transduction - genetics; Sox9 protein; Transcription Factor RelA - genetics; Transcription factors; Transcriptional activation; Tumor necrosis factor-TNF; Tumors; Young Adult; Zinc Finger Protein GLI1 - genetics
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.01.016

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. •Discovery of the first sense promoter-associated ncRNA derived from GLI1 (paGLI1), which is overexpressed in diffusely infiltrating gliomas.•PaGLI1 promotes GLI1 gene transcription by interacting with paGLI1 DNA, binding to and recruitment of transcription factor complex FUS/P65 to the GLI1 promoter, which results in enhancement of glioma cell proliferation and invasiveness.•Over-expression of paGLI1 is a significant unfavorable prognosticator for both disease-specific and progression-free survival in glioma patients.