Malignant melanoma, the most aggressive form of skin cancer, is characterized by high prevalence of BRAF/NRAS mutations and hyperactivation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), mitogen-activated protein kinases (MAPK), leading to uncontrolled melanoma growth. Efficacy of current targeted therapies against mutant BRAF or MEK1/2 have been hindered by existence of innate or development of acquired resistance. Therefore, a better understanding of the mechanisms controlled by MAPK pathway driving melanogenesis will help develop new treatment approaches targeting this oncogenic cascade. Here, we identify E3 ubiquitin ligase PARK2 as a direct target of ELK1, a known transcriptional effector of MAPK signaling in melanoma cells. We show that pharmacological inhibition of BRAF-V600E or ERK1/2 in melanoma cells increases PARK2 expression. PARK2 overexpression reduces melanoma cell growth in vitro and in vivo and induces apoptosis. Conversely, its genetic silencing increases melanoma cell proliferation and reduces cell death. Further, we demonstrate that ELK1 is required by the BRAF-ERK1/2 pathway to repress PARK2 expression and promoter activity in melanoma cells. Clinically, PARK2 is highly expressed in WT BRAF and NRAS melanomas, but it is expressed at low levels in melanomas carrying BRAF/NRAS mutations. Overall, our data provide new insights into the tumor suppressive role of PARK2 in malignant melanoma and uncover a novel mechanism for the negative regulation of PARK2 via the ERK1/2-ELK1 axis. These findings suggest that reactivation of PARK2 may be a promising therapeutic approach to counteract melanoma growth.

中文翻译：

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E3 泛素连接酶 PARK2 是黑色素瘤细胞生长的抑制剂，被致癌 ERK1/2-ELK1 转录轴抑制。

恶性黑色素瘤是最具侵袭性的皮肤癌，其特征是 BRAF/NRAS 突变的高发率和细胞外信号调节激酶 1 和 2 (ERK1/2)、丝裂原活化蛋白激酶 (MAPK) 的过度激活，导致不受控制的黑色素瘤生长。目前针对突变 BRAF 或 MEK1/2 的靶向疗法的疗效受到先天性耐药性或获得性耐药性的发展的阻碍。因此，更好地了解由 MAPK 通路驱动黑色素生成的机制将有助于开发针对这种致癌级联的新治疗方法。在这里，我们将 E3 泛素连接酶 PARK2 鉴定为 ELK1 的直接靶标，ELK1 是黑色素瘤细胞中 MAPK 信号传导的已知转录效应物。我们表明黑色素瘤细胞中 BRAF-V600E 或 ERK1/2 的药理学抑制会增加 PARK2 的表达。PARK2 过表达在体外和体内减少黑色素瘤细胞的生长并诱导细胞凋亡。相反，它的基因沉默会增加黑色素瘤细胞的增殖并减少细胞死亡。此外，我们证明 BRAF-ERK1/2 通路需要 ELK1 来抑制黑色素瘤细胞中的 PARK2 表达和启动子活性。临床上，PARK2在WT BRAF和NRAS黑色素瘤中高表达，但在携带BRAF/NRAS突变的黑色素瘤中低表达。总的来说，我们的数据为 PARK2 在恶性黑色素瘤中的肿瘤抑制作用提供了新的见解，并揭示了一种通过 ERK1/2-ELK1 轴负调控 PARK2 的新机制。