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Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization

Although melanoma therapy is improved by novel molecular targeted reagents, including vemurafenib, aberrant proliferation and early metastasis remain obstacles for melanoma; therefore, novel target molecules for melanoma need to be identified. In this study, we focused on deubiquitinating enzymes, w...

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Autores principales: Yokoyama, Satoru, Iwakami, Yusuke, Hang, Zhao, Kin, Ryoei, Zhou, Yue, Yasuta, Yutaka, Takahashi, Atsushi, Hayakawa, Yoshihiro, Sakurai, Hiroaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644625/
https://www.ncbi.nlm.nih.gov/pubmed/33154524
http://dx.doi.org/10.1038/s41598-020-76373-y
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author Yokoyama, Satoru
Iwakami, Yusuke
Hang, Zhao
Kin, Ryoei
Zhou, Yue
Yasuta, Yutaka
Takahashi, Atsushi
Hayakawa, Yoshihiro
Sakurai, Hiroaki
author_facet Yokoyama, Satoru
Iwakami, Yusuke
Hang, Zhao
Kin, Ryoei
Zhou, Yue
Yasuta, Yutaka
Takahashi, Atsushi
Hayakawa, Yoshihiro
Sakurai, Hiroaki
author_sort Yokoyama, Satoru
collection PubMed
description Although melanoma therapy is improved by novel molecular targeted reagents, including vemurafenib, aberrant proliferation and early metastasis remain obstacles for melanoma; therefore, novel target molecules for melanoma need to be identified. In this study, we focused on deubiquitinating enzymes, which regulate protein stability through ubiquitin–proteasome systems, and identified 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) as a molecule related to melanoma growth using siRNA library screening. Similar to a previous report, PSMD14 knockdown strongly induced p21 expression and inhibited RB phosphorylation in melanoma. After in silico analysis, TGF-β signaling was identified as a negatively correlated gene set with PSMD14 expression. Although TGF-β signaling is also related to the invasive phenotype of melanoma, PSMD14 knockdown suppressed melanoma migration and reduced SLUG expression, suggesting that targeting PSMD14 suppresses both growth and migration. Furthermore, SMAD3 expression increased in nucleus and SMAD3 degradation was delayed after PSMD14 knockdown. Thus, our present study suggests that targeting PSMD14 can inhibit melanoma growth and migration through either SMAD3 accumulation or SLUG reduction, respectively.
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spelling pubmed-76446252020-11-06 Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization Yokoyama, Satoru Iwakami, Yusuke Hang, Zhao Kin, Ryoei Zhou, Yue Yasuta, Yutaka Takahashi, Atsushi Hayakawa, Yoshihiro Sakurai, Hiroaki Sci Rep Article Although melanoma therapy is improved by novel molecular targeted reagents, including vemurafenib, aberrant proliferation and early metastasis remain obstacles for melanoma; therefore, novel target molecules for melanoma need to be identified. In this study, we focused on deubiquitinating enzymes, which regulate protein stability through ubiquitin–proteasome systems, and identified 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) as a molecule related to melanoma growth using siRNA library screening. Similar to a previous report, PSMD14 knockdown strongly induced p21 expression and inhibited RB phosphorylation in melanoma. After in silico analysis, TGF-β signaling was identified as a negatively correlated gene set with PSMD14 expression. Although TGF-β signaling is also related to the invasive phenotype of melanoma, PSMD14 knockdown suppressed melanoma migration and reduced SLUG expression, suggesting that targeting PSMD14 suppresses both growth and migration. Furthermore, SMAD3 expression increased in nucleus and SMAD3 degradation was delayed after PSMD14 knockdown. Thus, our present study suggests that targeting PSMD14 can inhibit melanoma growth and migration through either SMAD3 accumulation or SLUG reduction, respectively. Nature Publishing Group UK 2020-11-05 /pmc/articles/PMC7644625/ /pubmed/33154524 http://dx.doi.org/10.1038/s41598-020-76373-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yokoyama, Satoru
Iwakami, Yusuke
Hang, Zhao
Kin, Ryoei
Zhou, Yue
Yasuta, Yutaka
Takahashi, Atsushi
Hayakawa, Yoshihiro
Sakurai, Hiroaki
Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization
title Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization
title_full Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization
title_fullStr Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization
title_full_unstemmed Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization
title_short Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization
title_sort targeting psmd14 inhibits melanoma growth through smad3 stabilization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644625/
https://www.ncbi.nlm.nih.gov/pubmed/33154524
http://dx.doi.org/10.1038/s41598-020-76373-y
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