Abstract
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.
Highlights
Cancer initiation and progression depends on the balance of multiple pro-tumour and anti-tumour processes
HECTD2 expression defines transcriptional clusters in Skin cutaneous melanoma (SKCM) To investigate the basis for the association of HECTD2 expression with SKCM survival, we first examined whether it marked disease subsets
The the cancer genome atlas [25] (TCGA)-defined [25] ‘keratin’ subtype was underrepresented in clusters 2 and 4, whereas the ‘melanocyte inducing transcription factor (MITF)-low’ subtype was almost exclusive to these high HECTD2-expressing clusters (Fig. 1b)
Summary
Cancer initiation and progression depends on the balance of multiple pro-tumour and anti-tumour processes. These include cancer cell-intrinsic mechanisms regulating cell proliferation, survival and migration [1, 2], and extrinsic factors, such as stromal cells in the tumour microenvironment and the anti-tumour immune response [3,4,5,6]. These processes are connected and a clear link between cancer cell-intrinsic genetic programs and antitumour immunity is beginning to emerge [7,8,9]. The full extent of such bidirectional communication is incompletely understood and its outcome specific to the type of cancer [13]
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