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PEG3 inhibits mitophagy of papillary thyroid carcinoma through ISG15/VCP axis
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DOI：10.1007/s00018-026-06368-x.png)
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Abstract
En 中文
Interferon-stimulated gene 15 (ISG15) is an essential biomarker in several cancers. However, the molecular mechanism of ISG15 regulating thyroid carcinoma (THCA) has rarely been studied. In our study, papillary thyroid carcinoma cell lines of TPC-1 and IHH-4, clinical samples of THCA, and nude mice were employed. The expression levels of genes were tested by real-time quantitative PCR and western blotting analyses. Cell activity was assessed using cell counting kit-8 assay and colony formation assays. Flow cytometry measured the ROS level and mitochondrial membrane potential. To induce mitophagy, cells were treated with 10µM CCCP (Carbonyl Cyanide m-Chlorophenylhydrazone) for 6 h. The level of mitophagy was assessed by transmission electron microscopy, LC3B-TOMM20 co-localization, mitochondrial Parkin level, p-S65-Ub and related protein expression. Co-immunoprecipitation assays determined the binding relationship between ISG15 and VCP. Chromatin immunoprecipitation, electrophoretic mobility shift and dual-luciferase reporter assay measured the targeting of PEG3 on the ISG15 promoter. Our results showed that ISG15 was highly expressed in THCA. ISG15 overexpression promoted cell proliferation and mitophagy. Mechanistically, ISG15 bound to VCP and promoted its stability. VCP integrated with ISG15 to promote cell viability, and mitophagy. Further experiments revealed that PEG3, which acted as a transcriptional inhibitor of ISG15, exerted an effect opposing that of ISG15. The role of ISG15 and PEG3 were also confirmed in xenograft mice model. In conclusion, our present study explored the molecular mechanism of ISG15 on THCA and found that PEG3 transcriptionally regulated ISG15 and promoted the proliferation and mitophagy of papillary thyroid carcinoma cells through VCP. Our present study revealed a novel mechanism of ISG15 on THCA, which might be a promising therapeutic target for THCA.
Keywords:
PTC
Gene transcription
Mitophagy
Protein interaction
Protein stability
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