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J Clin Invest. 2018 Jan 2;128(1):517-530. doi: 10.1172/JCI95410. Epub 2017 Dec 11.

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth.

Author information

1
Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
2
Technion Integrated Cancer Center, Technion Israel Institute of Technology, Haifa, Israel.
3
Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, National Cancer Institute, Bethesda, Maryland, USA.
4
Department of Internal Medicine, Section of Medical Oncology, Yale University, New Haven, Connecticut, USA.
5
Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China.
6
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Abstract

SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.

KEYWORDS:

Cancer; Cell Biology; Melanoma; Oncology; Signal transduction

PMID:
29227283
PMCID:
PMC5749505
DOI:
10.1172/JCI95410
[Indexed for MEDLINE]
Free PMC Article

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