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  3. Palmitoylation modification of SPI1 promotes nasopharyngeal carcinoma radioresistance through inhibiting c-CBL-mediated ubiquitination and degradation

Palmitoylation modification of SPI1 promotes nasopharyngeal carcinoma radioresistance through inhibiting c-CBL-mediated ubiquitination and degradation

  • Drug Resist Updat. 2026 May:86:101374. doi: 10.1016/j.drup.2026.101374.
Li Jiang 1,  Ying Bin 2,  Yaoyi Huang 2,  Lanhua Wu 3,  Xingyue Qiu 3,  Youchang Du 2,  Jinglin Mi 2,  Kang Liu 2,  Yayan Deng 2,  Jiancheng Ning 2,  Mingxuan Li 2,  Zhen Meng 2,  Yating Qin 2,  Huisi Zhang 2,  Tianyu Wu 2,  Ding Liang 2,  Zuoting Cao 2,  Min Kang 4
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China; Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent, Nanning, Guangxi 530021, China; State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 2 Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 3 Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China; Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent, Nanning, Guangxi 530021, China.
  • 4 Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China; State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi 530021, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi 530021, China. Electronic address: [email protected].
PMID: 41691772 DOI: 10.1016/j.drup.2026.101374
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.

Keywords

SPI1; WWC2; angiogenesis; palmitoylation; radioresistance.

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