Incidence of melanoma continues to rise in the United States with ~100,000 new cases diagnosed in 2019. While the 5‐year survival rate of melanoma is 99% when localized, the rate of survival drops to 22.5% when distant disease is detected. As such, an area of great interest is understanding the mechanisms that promote melanoma metastasis so that better potential therapeutic targets can be discovered. Herein, we demonstrate that activation of NRF2 by FAM129B contributes to increased metastatic potential of BRAF V600E mutant melanoma cells. Specifically, FAM129B induces NRF2 by competing for Kelch‐like ECH‐associated protein 1 (KEAP1) binding (the negative regulator of NRF2) via an ETGE motif. Furthermore, we show that phosphorylation of FAM129B plays a role in mediating the interaction between FAM129B and KEAP1, as the phosphorylation status of FAM129B dictates its subcellular localization. When phosphorylated, FAM129B is found primarily in the cytosol where it can bind to KEAP1, but upon inhibition of mitogen‐activated protein kinase kinase activity, FAM129B is localized to the cell membrane and no longer interacts with KEAP1. In BRAF V600E mutant melanoma, the mitogen‐activated protein kinase pathway leads to hyperphosphorylation of FAM129B, and therefore FAM129B localizes to the cytosol, binds KEAP1, and upregulates NRF2. Importantly, genetic modulation or pharmacological inhibition that results in a decrease in FAM129B protein level or its phosphorylation decreases migration and invasion of mutant melanoma in an NRF2‐dependent manner. Overall, these data indicate that phosphorylation of FAM129B plays a significant role in driving the metastatic potential of BRAF V600E melanoma via upregulation of the NRF2 signaling pathway.

中文翻译：

---

NRF2的FAM129B依赖性激活促进了BRAF突变黑色素瘤细胞的侵袭性表型

美国黑色素瘤的发病率继续上升，2019 年诊断出约 100,000 例新病例。虽然局部黑色素瘤的 5 年存活率为 99%，但当检测到远处疾病时，存活率降至 22.5%。因此，一个非常感兴趣的领域是了解促进黑色素瘤转移的机制，以便发现更好的潜在治疗靶点。在此，我们证明 FAM129B 对 NRF2 的激活有助于增加 BRAF V600E 突变黑色素瘤细胞的转移潜能。具体来说，FAM129B 通过 ETGE 基序竞争 Kelch 样 ECH 相关蛋白 1 (KEAP1) 结合（NRF2 的负调节因子）来诱导 NRF2。此外，我们表明 FAM129B 的磷酸化在介导 FAM129B 和 KEAP1 之间的相互作用中起作用，因为 FAM129B 的磷酸化状态决定了它的亚细胞定位。当被磷酸化时，FAM129B 主要存在于细胞质中，它可以与 KEAP1 结合，但在抑制丝裂原活化蛋白激酶激酶活性后，FAM129B 定位于细胞膜，不再与 KEAP1 相互作用。在 BRAF V600E 突变黑色素瘤中，丝裂原活化蛋白激酶途径导致 FAM129B 过度磷酸化，因此 FAM129B 定位于细胞质，结合 KEAP1，并上调 NRF2。重要的是，导致 FAM129B 蛋白水平或其磷酸化降低的基因调节或药理学抑制以 NRF2 依赖性方式减少突变黑色素瘤的迁移和侵袭。总体，