E3 ubiquitin ligase PARK2, an inhibitor of melanoma cell growth, is repressed by the oncogenic ERK1/2-ELK1 transcriptional axis

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 wild type 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.

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

“…Moreover, the inhibition of the BRAF-ERK1/2 axis increases PARK2 expression. The authors showed that overexpression of PARK2 in melanoma cells was associated with an antiproliferative effect and cell death in vitro and in vivo [ 61 ]. Thus, the reactivation of PARK2 may be an effective approach to counteract melanoma progression.…”

The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer

“…Few pieces of evidence regarding Elk1 in proteasome inhibitor resistance have been published up to this day; however, the interaction between ERK1/2-Elk1 and the proteasome has already been proven (110). A study about…”

A novel circular RNA circPPFIA1 promotes laryngeal squamous cell carcinoma progression through sponging miR-340-3p and regulating ELK1 expression

“…To further elucidate the underlying mechanism for this, we predicted the target genes of miR-340-3p and focused on ELK1 as a potential target gene. ELK1 is a transcription factor that can be activated by the MAPK/ERK pathway, further activating the transcription of downstream genes such as c-Fos, cancerous inhibitor of protein phosphatase 2A (CIP2A) [ 26 ], and the E3 ubiquitin ligase PARK2 [ 27 ], and can also interact with other proteins such as thyroid transcription factor FOXE1 or aPKC-iota to co-regulate TERT and aPKC expression, respectively [ 28 , 29 ]. ELK1 plays a crucial role in the development of human cancers.…”