Therapeutic targeting of CNBP phase separation inhibits ribosome biogenesis and neuroblastoma progression via modulating SWI/SNF complex activity. Issue 4 (26th April 2023)

• Record Type: Journal Article
• Authors: Hu, Anpei; Chen, Guo; Bao, Banghe; Guo, Yanhua; Li, Dan; Wang, Xiaojing; Wang, Jianqun; Li, Qilan; Zhou, Yi; Gao, Haiyang; Song, Jiyu; Du, Xinyi; Zheng, Liduan; Tong, Qiangsong
• Is Part Of: Clinical and translational medicine. Volume 13:Issue 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-04-26
• Subjects: cellular nucleic acid‐binding protein -- karyopherin subunit beta 1 -- phase separation -- ribosome biogenesis -- SWI/SNF complex -- tumour progression; Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.1235
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract: Background: Neuroblastoma (NB) is the most common extracranial malignancy in childhood; however, the mechanisms underlying its aggressive characteristics still remain elusive. Methods: Integrative data analysis was performed to reveal tumour‐driving transcriptional regulators. Co‐immunoprecipitation and mass spectrometry assays were applied for protein interaction studies. Real‐time reverse transcription‐polymerase chain reaction, western blotting, sequential chromatin immunoprecipitation and dual‐luciferase reporter assays were carried out to explore gene expression regulation. The biological characteristics of NB cell lines were examined via gain‐ and loss‐of‐function assays. For survival analysis, the Cox regression model and log‐rank tests were used. Results: Cellular nucleic acid‐binding protein ( CNBP ) was found to be an independent factor affecting NB outcome, which exerted oncogenic roles in ribosome biogenesis, tumourigenesis and aggressiveness. Mechanistically, karyopherin subunit beta 1 (KPNB1) was responsible for nuclear transport of CNBP, whereas liquid condensates of CNBP repressed the activity of switch/sucrose‐nonfermentable (SWI/SNF) core subunits (SMARCC2/SMARCC1/SMARCA4) via interaction with SMARCC2, leading to alternatively increased activity of SMARCC1/SMARCA4 binary complex in facilitating gene expression essential for 18S ribosomal RNA (rRNA) processing in tumour cells, extracellular vesicle‐mediated delivery of 18S rRNA and subsequent M2 macrophage polarisation. A cell‐penetrating peptide blocking phase separation and interaction of CNBP with SMARCC2 inhibited ribosome biogenesis and NB progression. High KPNB1, CNBP, SMARCC1 or SMARCA4 expression or low SMARCC2 levels were associated with poor survival of NB patients. Conclusions: These findings suggest that CNBP phase separation is a target for inhibiting ribosome biogenesis and tumour progression in NB via modulating SWI/SNF complex activity. Abstract : 1. CNBP is associated with poor prognosis and clinical progression of neuroblastoma. 2. KPNB1 facilitates nuclear translocation of CNBP to interact with SMARCC2 in liquid condensates. 3. CNBP modulates SWI/SNF activity via SMARCC2 to drive ribosome biogenesis of neuroblastoma cells and subsequent M2 macrophage polarisation. 4. Therapeutic targeting of phase separation and interaction of CNBP with SMARCC2 inhibits neuroblastoma progression.