Palmitoylation modification of SPI1 promotes nasopharyngeal carcinoma radioresistance through inhibiting c-CBL-mediated ubiquitination and degradation
Abstract
AIMS Radioresistance remains a significant challenge in nasopharyngeal carcinoma (NPC) treatment, resulting in treatment failure and poor clinical outcomes. This study aims to explore and characterize the functional significance and molecular mechanism of SPI1 (a hematopoietic lineage transcription factor) in NPC radioresistance. METHODS RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence were performed to investigate expression of genes and proteins. Cell viability, apoptosis, migration, and tube formation were determined by MTT, flow cytometry, wound healing, transwell, and tube formation assays. Acyl Biotin Exchange (ABE) assay was used to determine palmitoylation levels of SPI1. Co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter, EMSA, and RNA pull-down were conducted to analyze the interaction between genes. RESULTS SPI1 was significantly upregulated in radioresistant NPC tissues and cells, correlating with a poor prognosis. Knockdown of SPI1 suppressed radioresistance in NPC cells and enhanced tumor radiosensitivity in vivo. Palmitoylation of SPI1 at C5 inhibited E3 ubiquitin ligase casitas B-lineage lymphoma (c-CBL)-mediated ubiquitination and degradation, causing SPI1 upregulation in radioresistant NPC cells. SPI1 increased miR-205-5p expression and exosomal enrichment in radioresistant NPC cells, subsequently enhancing endothelial cell angiogenesis. Engineered exosomes carrying miR-205-5p inhibitor suppressed angiogenesis and radioresistance in xenograft models by inhibiting the WW domain-containing protein 2 (WWC2)-mediated Hippo pathway. CONCLUSIONS Collectively, our findings suggest that SPI1 palmitoylation inhibits c-CBL-mediated ubiquitination and degradation, thereby enhancing SPI1 protein stability and its transcriptional regulation of miR-205-5p. Upregulated miR-205-5p in NPC cells is packaged into exosomes and transferred to endothelial cells, where it targets and inhibits WWC2 expression, eventually promoting angiogenesis and NPC radioresistance.
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Research works printed but not linked: 1
- Xu, 2023, Palmitoyltransferase ZDHHC3 aggravates nonalcoholic steatohepatitis by targeting S-palmitoylated IRHOM2, Adv. Sci. (Weinh. ), 10
- Authors
- Jiang, L., Bin, Y., Huang, Y., Wu, L., Qiu, X., Du, Y., Mi, J., Liu, K., Deng, Y., Ning, J., Li, M., Meng, Z., Qin, Y., Zhang, H., Wu, T., Liang, D., Cao, Z., & Kang, M.
- Affiliations
- Guangxi Medical University (CN)
- Corresponding author
- Kang, Min
- Venue
- Drug Resistance Updates
- Publisher
- Elsevier BV
- Published
- 2026-05
- Volume
- 86
- Pages
- 101374
- ISSN
- 1368-7646 (ISSN-L)
- OpenAlex
- W7128095378
- Semantic Scholar
- 6a9e3d329df98d7164617337c283e6f6bb05cda5
- Cited by
- 0
- References
- 42
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Drug Resistance Updates (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Guangxi Medical University (2023, 2024)
- Science Fund for Distinguished Young Scholars of Guangxi Province (2025GXNSFFA069001)
- China Postdoctoral Science Foundation (2024MD763945)
- Natural Science Foundation of Guangxi Province
- Scientific Research and Technology Development Program of Guangxi Zhuang Autonomous Region
- National Natural Science Foundation of China (82202940)
- Topics
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- PU.1, palmitoylation, nasopharyngeal carcinoma, radioresistance (biology), c-Cbl, ubiquitination, protein degradation, miR-205-5p
- MeSH terms
- Nasopharyngeal Carcinoma, Animals
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