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SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth
Hironari Tamiya, … , Kazuhiro Iwai, Ze’ev A. Ronai
Hironari Tamiya, … , Kazuhiro Iwai, Ze’ev A. Ronai
Published December 11, 2017
Citation Information: J Clin Invest. 2018;128(1):517-530. https://doi.org/10.1172/JCI95410.
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Research Article Cell biology Oncology

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

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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.

Authors

Hironari Tamiya, Hyungsoo Kim, Oleksiy Klymenko, Heejung Kim, Yongmei Feng, Tongwu Zhang, Jee Yun Han, Ayako Murao, Scott J. Snipas, Lucia Jilaveanu, Kevin Brown, Harriet Kluger, Hao Zhang, Kazuhiro Iwai, Ze’ev A. Ronai

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Figure 1

SHARPIN is upregulated in melanoma.

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SHARPIN is upregulated in melanoma.
(A) Upper panel: SHARPIN transcript ...
(A) Upper panel: SHARPIN transcript levels in diverse cancer types (red dots, n = approximately 169–998, TCGA) and normal tissue (green dots, n = approximately 0–155) (2-tailed Mann-Whitney U test). Lower panel: HOIP, HOIL-1L, and SHARPIN transcript levels in normal tissue (n = 7), benign nevi (n = 18), and melanoma (n = 45) (GDS1375 data set). One-way ANOVA with Dunnett’s test. (B) Immunoblot (upper panel) and qPCR (lower panel) analysis of LUBAC components in melanocytes (NHEM) and the indicated melanoma cell lines. Tubulin was probed as a loading control. qPCR data are presented as relative mRNA levels compared with NHEM cells. Data are representative results from 2 experiments. **P < 0.005; ***P < 0.0005. NA, not applicable.
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