Therapeutic targeting of CNBP phase separation inhibits ribosome biogenesis and neuroblastoma progression via modulating SWI/SNF complex activity

Author:

Hu Anpei1,Chen Guo1,Bao Banghe2,Guo Yanhua1,Li Dan1,Wang Xiaojing13,Wang Jianqun1,Li Qilan1,Zhou Yi2,Gao Haiyang4,Song Jiyu2,Du Xinyi1,Zheng Liduan23,Tong Qiangsong13ORCID

Affiliation:

1. Department of Pediatric Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan Hubei Province P. R. China

2. Department of Pathology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan Hubei Province P. R. China

3. Clinical Center of Human Genomic Research Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan Hubei Province P. R. China

4. Department of Gastrointestinal Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan Hubei Province P. R. China

Abstract

AbstractBackgroundNeuroblastoma (NB) is the most common extracranial malignancy in childhood; however, the mechanisms underlying its aggressive characteristics still remain elusive.MethodsIntegrative 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.ResultsCellular 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.ConclusionsThese findings suggest that CNBP phase separation is a target for inhibiting ribosome biogenesis and tumour progression in NB via modulating SWI/SNF complex activity.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Molecular Medicine,Medicine (miscellaneous)

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