Deficiency of parkin suppresses melanoma tumor development and metastasis through inhibition of MFN2 ubiquitination

Lee, Yong Sun; Jung, Yu Yeon; Park, Mi Hee; Yeo, In Jun; Im, Hyung; Nam, Kyung Tak; Kim, Hae Deun; Kang, Shin Kook; Song, Ju Koung; Kim, Yu Ri; Choi, Dong‐Young; Park, Pil-Hoon; Han, Sang‐Bae; Yun, Jae Suk; Hong, Jin Tae

doi:10.1016/j.canlet.2018.07.007

Cited by 31 publications

(25 citation statements)

References 37 publications

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“…A recent study proposed that PARK2inactivating mutations increase the risk of melanoma and that restoration of PARK2 expression in PARK2-deficient melanoma cell lines reduces colony formation (8). However, another report suggested an oncogenic role of PARK2 in melanoma (39). Our findings provide several lines of evidence supporting the tumor suppressive role of PARK2 in human melanoma.…”

Section: Discussionsupporting

confidence: 67%

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

Montagnani

Maresca

Apollo

et al. 2020

Journal of Biological Chemistry

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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.

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Section: Discussionsupporting

confidence: 67%

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

Montagnani

Maresca

Apollo

et al. 2020

Journal of Biological Chemistry

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“…In several cancer types, the degradation of damaged mitochondria and the recycling of metabolic precursors by mitophagy can promote cell survival and protect from cell death [110] [136]. In Parkindeficient mice melanoma growth and metastasis are suppressed, suggesting a pro-tumour role of Parkin-dependent mitophagy [137]. However, Parkin is often downregulated in many tumour types.…”

Section: Mitophagy In Cancermentioning

confidence: 99%

Autophagy and mitophagy in cancer metabolic remodelling

Ferro

Servais

Besson

et al. 2020

Seminars in Cell & Developmental Biology

198

130

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Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global metabolic adaptations allowing them to survive in the low oxygen and nutrient tumour microenvironment. Among these metabolic adaptations, cancer cells use glycolysis but also mitochondrial oxidations to produce ATP and building blocks needed for their high proliferation rate. Another particular adaptation of cancer cell metabolism is the use of autophagy and specific forms of autophagy like mitophagy to recycle intracellular components in condition of metabolic stress or during anticancer treatments. The plasticity of cancer cell metabolism is a major limitation of anticancer treatments and could participate to therapy resistances. The aim of this review is to report recent advances in the understanding of the relationship between tumour metabolism and autophagy/mitophagy in order to propose new therapeutic strategies.

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“…(B) Melanomagenesis from melanocytic nevi is blocked upon melanocytic-specific depletion of autophagy genes, such as Atg5 and Atg7 in GEMMs (64,65). Syngeneic models displayed similar evidence, as in the case of host mice injected with Beclin1-engineered B16-F10 melanoma cells (67) or upon injection of melanoma cells in Atg7-and Parkin-genetically engineered mice (68,69). (C) Melanoma development is favored upon single-copy loss of Atg5 in GEMM (65).…”

Section: Autophagy During Melanoma Evolution: a Tumor Suppressive Role?mentioning

confidence: 94%

“…As such, mitophagy can be exploited by cancer cells to isolate and degrade damaged mitochondria to ensure qualitatively functional organelles. Indeed, a reduced proliferative rate has been associated with compromised fission machinery and retention of dysfunctional mitochondria in melanoma cell lines (69,73). Also, increased hyper-activation of the fission machinery, which has been positively correlated to the BRAF V600E mutation in human patients, has been implicated in high proliferation of melanoma cells (79).…”

Section: Mitochondria In Melanomamentioning

confidence: 99%

“…Doing so, BNIP3 favors mitochondrial fitness and maintains survival, bioenergetics, growth and aggressiveness of melanoma cells (80,81). In parallel, Lee et al have recently used an elaborate syngeneic model of B16-F10 melanoma cells injected in a transgenic Parkin knock-out mouse and assessed that Parkin favors melanoma growth and distal metastases by preventing the activation of the apoptotic cascade (Figure 1B) (69).…”

Section: Mitochondria In Melanomamentioning

confidence: 99%

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The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

2020

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Despite tremendous efforts in the last decade to improve treatments, melanoma still represents a major therapeutic challenge and overall survival of patients remains poor. Therefore, identifying new targets to counteract melanoma is needed. In this scenario, autophagy, the "self-eating" process of the cell, has recently arisen as new potential candidate in melanoma. Alongside its role as a recycling mechanism for dysfunctional and damaged cell components, autophagy also clearly sits at a crossroad with metabolism, thereby orchestrating cell proliferation, bioenergetics and metabolic rewiring, all hallmarks of cancer cells. In this regard, autophagy, both in tumor and host, has been flagged as an essential player in melanomagenesis and progression. To pave the way to a better understanding of such a complex interplay, the use of genetically engineered mouse models (GEMMs), as well as syngeneic mouse models, has been undoubtedly crucial. Herein, we will explore the latest discoveries in the field, with particular focus on the potential of these models in unraveling the contribution of autophagy in melanoma, along with the therapeutic advantages that may arise.

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Deficiency of parkin suppresses melanoma tumor development and metastasis through inhibition of MFN2 ubiquitination

Cited by 31 publications

References 37 publications

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

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

Autophagy and mitophagy in cancer metabolic remodelling

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

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