OTUD4 stabilizes CYLD and counteracts BCL3 K63-linked polyubiquitination to suppress melanoma progression
- 1Changsha, China
Abstract
Melanoma is a highly aggressive malignancy in which dysregulated ubiquitin-dependent signaling contributes to tumor progression. OTUD4 is frequently downregulated in melanoma, but the functional significance of this alteration remains unclear. Here, we identify OTUD4 as a dual-mode deubiquitinase that suppresses melanoma progression by coordinating K48- and K63-linked polyubiquitination. OTUD4 directly binds and stabilizes CYLD by counteracting K48-linked polyubiquitination, whereas it independently binds BCL3 and counteracts BCL3 K63-linked polyubiquitination. OTUD4 depletion promotes BCL3 ubiquitination and nuclear translocation in melanoma cells, leading to increased melanoma cell proliferation and tumor growth in clonogenic and xenograft assays. Clinically, expression of OTUD4 and CYLD progressively decreases from normal skin through benign nevi to melanoma, with a further reduction in highly metastatic tumors. Reduced expression of OTUD4 and CYLD is associated with poor prognosis in patients with melanoma. Together, these results reveal an OTUD4–CYLD–BCL3 regulatory axis in melanoma, in which OTUD4 stabilizes CYLD and inhibits BCL3 activity.
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BibTeX
@article{he2026otud4,
title = {{OTUD4 stabilizes CYLD and counteracts BCL3 K63-linked polyubiquitination to suppress melanoma progression}},
author = {Yuming He and Lin Miao and Yunfang Deng and Yuyao Xue and Zhaohui Liu and Zhiming Sun and Chujing He and Hao Feng and Jiabing Li and Yuqiao Cai and Yaoyu Gu and Ke Li and Yu Zhao},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09130-0},
url = {https://europepmc.org/article/PMC/PMC13691072},
note = {CC BY},
}
RIS
TY - JOUR
TI - OTUD4 stabilizes CYLD and counteracts BCL3 K63-linked polyubiquitination to suppress melanoma progression
AU - Yuming He
AU - Lin Miao
AU - Yunfang Deng
AU - Yuyao Xue
AU - Zhaohui Liu
AU - Zhiming Sun
AU - Chujing He
AU - Hao Feng
AU - Jiabing Li
AU - Yuqiao Cai
AU - Yaoyu Gu
AU - Ke Li
AU - Yu Zhao
PY - 2026
DA - 2026/07/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09130-0
UR - https://europepmc.org/article/PMC/PMC13691072
AB - Melanoma is a highly aggressive malignancy in which dysregulated ubiquitin-dependent signaling contributes to tumor progression. OTUD4 is frequently downregulated in melanoma, but the functional significance of this alteration remains unclear. Here, we identify OTUD4 as a dual-mode deubiquitinase that suppresses melanoma progression by coordinating K48- and K63-linked polyubiquitination. OTUD4 directly binds and stabilizes CYLD by counteracting K48-linked polyubiquitination, whereas it independently binds BCL3 and counteracts BCL3 K63-linked polyubiquitination. OTUD4 depletion promotes BCL3 ubiquitination and nuclear translocation in melanoma cells, leading to increased melanoma cell proliferation and tumor growth in clonogenic and xenograft assays. Clinically, expression of OTUD4 and CYLD progressively decreases from normal skin through benign nevi to melanoma, with a further reduction in highly metastatic tumors. Reduced expression of OTUD4 and CYLD is associated with poor prognosis in patients with melanoma. Together, these results reveal an OTUD4–CYLD–BCL3 regulatory axis in melanoma, in which OTUD4 stabilizes CYLD and inhibits BCL3 activity.
SN - 2041-4889
ER -