Abstract
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.
Highlights
Malignant melanoma is the most aggressive form of skin cancer
Western blotting (WB) and quantitative real-time PCR analyses in melanoma cell lines showed that PARK2 expression is lower in cells harboring BRAFV600E or NRASQ61R mutations (SK-Mel-2, SK-Mel-5, SK-Mel-28, A375, 501-Mel) compared with those with WT BRAF or NRAS (M51, SSM2c, SK-Mel-197)
We provide the evidence that PARK2 is negatively modulated by the RAS-RAF-MEK1/2-extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling via the transcription factor ELK1
Summary
Malignant melanoma is the most aggressive form of skin cancer. The most prevalent genetic alterations in melanoma are mutually exclusive mutations in BRAF and NRAS, which occur in nearly 50 and 25% of melanoma patients, respectively [1]. PARK2 is negatively regulated by the ERK1/2-ELK1 axis showed reduced PARK2 mRNA expression in melanoma cell lines compared with normal human epidermal melanocytes (NHEM) (Fig. 1B). Treatment with SCH772984, an ERK1/2 inhibitor [21], consistently increased PARK2 protein levels in all four melanoma cell lines (Fig. 1H and Fig. S2B).
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