Feedforward loop between IMP1 and YAP/TAZ promotes tumorigenesis and malignant progression in glioblastoma

• Published in: Cancer science Vol. 114; no. 5; pp. 2053 - 2062
• Main Authors: Yang, Jia, Wu, Xujia, Wang, Jia, Guo, Xing, Chen, Junju, Yang, Xuesong, Zhong, Jian, Li, Xixi, Deng, Zhong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2023; John Wiley and Sons Inc
• Subjects: Antibodies; Brain cancer; Carcinogenesis - genetics; Cell Line, Tumor; Cell Transformation, Neoplastic; Datasets; Glioblastoma; Glioblastoma - metabolism; Glioma; Glioma cells; Humans; IMP1; Insulin-like growth factor II; Laboratory animals; malignant progression; N6-methyladenosine; Original; ORIGINAL ARTICLES; Phenotypes; Phosphoproteins - genetics; Phosphoproteins - metabolism; Post-transcription; Proteins; RNA polymerase; Signal Transduction; Survival analysis; Transcription Factors - genetics; Transcription Factors - metabolism; Tumorigenesis; Tumors; YAP-Signaling Proteins; YAP/TAZ pathway; Yes-associated protein; YAP/TAZ pathway; glioblastoma; malignant progression; IMP1
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15636

YAP/TAZ have been identified as master regulators in malignant phenotypes of glioblastoma (GBM); however, YAP/TAZ transcriptional disruptor in GBM treatment remains ineffective. Whether post‐transcriptional dysregulation of YAP/TAZ improves GBM outcome is currently unknown. Here, we report that insulin‐like growth factor 2 (IGF2) mRNA‐binding protein 1 (IGF2BP1 or IMP1) is upregulated in mesenchymal GBM compared with proneural GBM and correlates with worse patient outcome. Overexpression of IMP1 in proneural glioma stem‐like cells (GSCs) promotes while IMP1 knockdown in mesenchymal GSCs attenuates tumorigenesis and mesenchymal signatures. IMP1 binds to and stabilizes m6A‐YAP mRNA, leading to activation of YAP/TAZ signaling, depending on its m6A recognition and binding domain. On the other hand, TAZ functions as enhancer for IMP1 expression. Collectively, our data reveal a feedforward loop between IMP1 and YAP/TAZ maintaining GBM/GSC tumorigenesis and malignant progression and a promising molecular target in GBM. IMP1 is a highly expressed RNA‐binding protein in mesenchymal glioblastoma, which correlates with short survival. IMP1 binds to and stabilizes YAP m6A mRNA, leading to activation of YAP/TAZ signaling. YAP/TAZ and IMP1 form a feedforward loop, promoting stemness characteristics and mesenchymal‐like state in glioblastoma.