School of Pharmaceutical Sciences, Southern Medical University.
Department of Pharmacy, Nanfang Hospital, Southern Medical University.
Melanoma Res. 2021 Apr 1;31(2):119-129. doi: 10.1097/CMR.0000000000000714.
Although germline mutations in BRCA-associated protein-1 (BAP1) predispose to cutaneous melanoma (CM), BAP1 is rarely mutated in primary CM outside the familial context. The role of BAP1 in the pathogenesis of CM remains obscure. Here, we discovered an unexpected role of BAP1 in suppressing CM growth and metastasis. BAP1 deletion by CRISPR-Cas9 system severely compromises colony-forming capability of murine CM cell line B16-F10 and human CM cell lines, SK-MEL-28 and A375. Furthermore, BAP1 loss abrogates tumor growth and lung metastasis in murine syngeneic tumor models. Deletion of BAP1 in B16-F10 cells leads to preferential downregulation of genes accompanied with increased H2A ubiquitination at lysine 119. Transcriptomic characterization of BAP1 deletion reveals multiple deregulated cellular functions including extracellular matrix-receptor interaction and MAPK signaling pathway which may contribute to BAP1's effect on metastasis and proliferation. Our findings indicate that BAP1 could be a potential therapeutic target for CM.
虽然 BRCA 相关蛋白 1（BAP1）的种系突变易导致皮肤黑色素瘤（CM），但在家族性以外的原发性 CM 中，BAP1 很少发生突变。BAP1 在 CM 发病机制中的作用仍不清楚。在这里，我们发现了 BAP1 抑制 CM 生长和转移的意外作用。CRISPR-Cas9 系统对 BAP1 的缺失严重损害了鼠 CM 细胞系 B16-F10 和人 CM 细胞系 SK-MEL-28 和 A375 的集落形成能力。此外，BAP1 的缺失消除了鼠同源肿瘤模型中的肿瘤生长和肺转移。B16-F10 细胞中 BAP1 的缺失导致伴随赖氨酸 119 上 H2A 泛素化增加的基因优先下调。BAP1 缺失的转录组特征揭示了多种失调的细胞功能，包括细胞外基质-受体相互作用和 MAPK 信号通路，这可能有助于 BAP1 对转移和增殖的影响。我们的研究结果表明，BAP1 可能是 CM 的一个潜在治疗靶点。
