HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation.

Abstract

Cancer stem cells play crucial roles in tumorigenesis and aggressiveness, while regulatory mechanisms in neuroblastoma (NB), a pediatric extracranial malignancy with highest incidence, are still unknown. Herein, a small 51-amino acid peptide (sPEP1) encoded by hepatocyte nuclear factor 4 alpha antisense RNA 1 (HNF4A-AS1) was identified in tumor tissues and cells, which facilitated self-renewal and aggressiveness of NB stem cells. MiRNA-409-5p interacted with HNF4A-AS1 to facilitate sPEP1 translation via recruiting eukaryotic translation initiation factor 3 subunit G, while sPEP1 repressed serum deprivation-induced senescence and promoted sphere formation, growth, or metastasis of NB stem cells. Mechanistically, sPEP1 directly interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) to facilitate its binding to SMAD family member 4 (SMAD4), resulting in repression of SMAD4 transactivation and transcriptional upregulation of stem cell genes associated with tumor progression. Rescue experiments revealed that sPEP1 exerted oncogenic roles via facilitating physical interaction between eEF1A1 and SMAD4. Notably, knockdown of sPEP1 significantly repressed the self-renewal and metastasis of NB stem cells in vivo. High sPEP1 or eEF1A1 levels in clinical NB tissues were linked to poor patients' survival. These findings suggest that HNF4A-AS1-encoded sPEP1 promotes self-renewal and aggressive features of NB stem cells by eEF1A1-repressed SMAD4 transactivation.

• Authors: Huajie Song, Jianqun Wang, Xiaojing Wang, Boling Yuan, Dan Li, Anpei Hu, Yanhua Guo, Shuang Cai, Shikai Jin, Yi Zhou, Qilan Li, Guo Chen, Haiyang Gao, Liduan Zheng, Qiangsong Tong
• Journal: Oncogene (Oncogene) Vol. 41 Issue 17 Pg. 2505-2519 (04 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35318442 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• EEF1A1 protein, human
• HNF4A protein, human
• Hepatocyte Nuclear Factor 4
• MicroRNAs
• Peptide Elongation Factor 1
• RNA, Antisense
• RNA, Long Noncoding
• SMAD4 protein, human
• Smad4 Protein

Topics

• Carcinogenesis (genetics)
• Cell Line, Tumor
• Child
• Gene Expression Regulation, Neoplastic
• Hepatocyte Nuclear Factor 4 (genetics, metabolism)
• Humans
• MicroRNAs (genetics)
• Neuroblastoma (pathology)
• Peptide Elongation Factor 1 (genetics, metabolism)
• RNA, Antisense
• RNA, Long Noncoding (genetics)
• Smad4 Protein (genetics, metabolism)
• Stem Cells (metabolism)
• Transcriptional Activation