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.