黑色素瘤是皮肤癌症中最具侵袭性的形态，全球范围内，尤其是在高加索人群中，发病率迅速上升。在早期病变的患者中，手术切除是治愈性治疗的首选。然而，对于转移性黑色素瘤患者的治疗效果仍然不尽人意。因此，了解参与转移和化疗耐药的分子机制对黑色素瘤的新治疗方法至关重要。Snail1是一个重要的上皮-间充质转化转录因子（EMT-TFs），对于诱导 EMT 进程并促进癌症转移具有重要作用。然而，Snail1在黑色素瘤转移中的作用还不清楚，调控Snail1的潜在机制还需要进一步研究。 在这里，我们发现OTUD4是黑色素瘤中Snail1的一种新的去泛素化酶。此外，在体外和体内实验证明，OTUD4的缺失显著抑制了黑色素瘤细胞中Snail1的稳定性和Snail1驱动的恶性表型。总体而言，我们的研究确定了OTUD4作为黑色素瘤转移和化疗耐药的一个新的治疗靶点，通过稳定Snail1，并为黑色素瘤的潜在治疗策略提供了合理性依据。© 2023 Wiley Periodicals LLC.

Melanoma is the most aggressive form of skin cancer with rapidly increased incidence worldwide especially in the Caucasian population. Surgical excision represents the curative treatment choice in patients with early-stage disease. However, the therapeutic outcomes in patients with metastatic melanoma remains unsatisfactory. Thus, understanding molecular mechanisms contributing to metastasis and chemoresistance is critical for new improved therapies of melanoma. Snail1, an important epithelial-mesenchymal transition transcription factors (EMT-TFs), is critical to induce the EMT process, thereby contributing to cancer metastasis. However, the involvement of Snail1 in melanoma metastasis remains elusive and the underlying mechanism to regulate Snail1 in melanoma needs to be further investigated. Here, we identified OTUD4 as a novel deubiquitinase of Snail1 in melanoma. Moreover, the depletion of OTUD4 in melanoma cells markedly inhibited Snail1 stability and Snail1-driven malignant phenotypes both in vitro and in vivo. Overall, our study establishes OTUD4 as a novel therapeutic target in metastasis and chemoresistance of melanoma by stabilizing Snail1 and provides a rationale for potential therapeutic strategies of melanoma.© 2023 Wiley Periodicals LLC.