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E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion.

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journal contribution
posted on 23.09.2021, 10:13 by Eleonora Ottina, Veera Panova, Laura Doglio, Anastasiya Kazachenka, Georgina Cornish, Joanna Kirkpatrick, Jan Attig, George R Young, Kevin Litchfield, Tom Lesluyes, Peter Van Loo, Charles Swanton, James MacRae, Thomas Tüting, George Kassiotis
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.

Funding

Crick (Grant ID: 10202, Grant title: Van Loo FC001202) Crick (Grant ID: 10169, Grant title: Swanton FC001169) Crick (Grant ID: 10011, Grant title: STP Proteomics) Crick (Grant ID: 10012, Grant title: STP Metabolomics) Crick (Grant ID: 10099, Grant title: Kassiotis FC001099) Wellcome Trust (Grant ID: 102898/B/13/Z, Grant title: WT 102898/B/13/Z) Cancer Research UK (Grant ID: C55533/A22158, Grant title: CRUK C55533/A22158) Crick (Grant ID: 10162, Grant title: Stoye FC001162)

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