E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion
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Eleonora Ottina Veera Panova Laura Doglio Anastasiya Kazachenka Georgina Cornish Joanna Kirkpatrick Jan Attig George Young Kevin Litchfield Tom Lesluyes Peter Van Loo Charles Swanton James Macrae Thomas Tüting George KassiotisAbstract
The ubiquitin-proteasome system maintains protein homoeostasis, underpins the cell cycle, and is dysregulated in cancer. However, the role of individual E3 ubiquitin ligases, which mediate the final step in ubiquitin-mediated proteolysis, remains incompletely understood. Identified through screening for cancer-specific endogenous retroviral transcripts, we show that the little-studied E3 ubiquitin ligase HECTD2 exerts dominant control of tumour progression in melanoma. HECTD2 cell autonomously drives the proliferation of human and murine melanoma cells by accelerating the cell cycle. HECTD2 additionally regulates cancer cell production of immune mediators, initiating multiple immune suppressive pathways, which include the cyclooxygenase 2 (COX2) pathway. Accordingly, higher HECTD2 expression is associated with weaker anti-tumour immunity and unfavourable outcome of PD-1 blockade in human melanoma and counteracts immunity against a model tumour antigen in murine melanoma. This central, multifaceted role of HECTD2 in cancer cell-autonomous proliferation and in immune evasion may provide a single target for a multipronged therapy of melanoma.
Journal details
Journal Oncogene
Volume 40
Issue number 37
Pages 5567-5578
Available online
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Publisher website (DOI) 10.1038/s41388-021-01885-4
Europe PubMed Central 34145398
Pubmed 34145398
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- Tumour Biology
- Structural Biology & Biophysics
- Signalling & Oncogenes
- Model Organisms
- Metabolism
- Infectious Disease
- Immunology
- Human Biology & Physiology
- Genome Integrity & Repair
- Genetics & Genomics
- Developmental Biology
- Computational & Systems Biology
- Chemical Biology & High Throughput
- Cell Biology
- Biochemistry & Proteomics
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