PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis
Abstract Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionally high mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role of Proprotein Convertase Subtilisin/...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07690-1 |
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| Summary: | Abstract Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionally high mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in ATC progression. Proteomic analysis revealed E-cadherin as a key mediator of PCSK9-driven malignancy in ATC. Mechanistically, PCSK9 promotes the degradation of E-cadherin through the lysosomal pathway. Furthermore, the loss of the p53 function, particularly the R248Q mutation, de-repressed PCSK9 expression at the transcriptional level. Notably, the PCSK9 inhibitor PF-846 considerably suppressed ATC proliferation and metastasis in both in vitro and in vivo models. In conclusion, PCSK9 enhances ATC malignancy by regulating E-cadherin degradation via the lysosomal pathway, underscoring its potential as a promising therapeutic target. |
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| ISSN: | 2041-4889 |