BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway

Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1...

Descripción completa

Detalles Bibliográficos
Autores principales: Deng, Guangtong, Zeng, Furong, Su, Juan, Zhao, Shuang, Hu, Rui, Zhu, Wu, Hu, Shuo, Chen, Xiang, Yin, Mingzhu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546000/
https://www.ncbi.nlm.nih.gov/pubmed/33052224
http://dx.doi.org/10.7150/thno.47432
_version_ 1783592146406735872
author Deng, Guangtong
Zeng, Furong
Su, Juan
Zhao, Shuang
Hu, Rui
Zhu, Wu
Hu, Shuo
Chen, Xiang
Yin, Mingzhu
author_facet Deng, Guangtong
Zeng, Furong
Su, Juan
Zhao, Shuang
Hu, Rui
Zhu, Wu
Hu, Shuo
Chen, Xiang
Yin, Mingzhu
author_sort Deng, Guangtong
collection PubMed
description Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1) as a melanoma driver and a crucial target of BET inhibitors in melanoma. Methods: Bioinformatics analysis and meta-analysis were used to evaluate the SPP1 expression in normal tissues, primary melanoma, and metastatic melanoma. Real-time PCR (RT-PCR) and Western blotting were employed to quantify SPP1 expression in melanoma cells and tissues. Cell proliferation, wound healing, and Transwell assays were carried out to evaluate the effects of SPP1 and BET inhibitors in melanoma cells in vitro. A xenograft mouse model was used to investigate the effect of SPP1 and BET inhibitors on melanoma in vivo. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the regulatory mechanism of BET inhibitors on SPP1. Results: SPP1 was identified as a melanoma driver by bioinformatics analysis, and meta-analysis determined it to be a diagnostic and prognostic biomarker for melanoma. SPP1 overexpression was associated with poor melanoma prognosis, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion. Through a pilot drug screen, we identified BET inhibitors as ideal therapeutic agents that suppressed SPP1 expression. Also, SPP1 overexpression could partially reverse the suppressive effect of BET inhibitors on melanoma. We further demonstrated that bromodomain-containing 4 (BRD4) regulated SPP1 expression. Notably, BRD4 did not bind directly to the SPP1 promoter but regulated SPP1 expression through NFKB2. Silencing of NFKB2 resembled the phenotype of BET inhibitors treatment and SPP1 silencing in melanoma. Conclusion: Our findings highlight SPP1 as an essential target of BET inhibitors and provide a novel mechanism by which BET inhibitors suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway.
format Online
Article
Text
id pubmed-7546000
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-75460002020-10-12 BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway Deng, Guangtong Zeng, Furong Su, Juan Zhao, Shuang Hu, Rui Zhu, Wu Hu, Shuo Chen, Xiang Yin, Mingzhu Theranostics Research Paper Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1) as a melanoma driver and a crucial target of BET inhibitors in melanoma. Methods: Bioinformatics analysis and meta-analysis were used to evaluate the SPP1 expression in normal tissues, primary melanoma, and metastatic melanoma. Real-time PCR (RT-PCR) and Western blotting were employed to quantify SPP1 expression in melanoma cells and tissues. Cell proliferation, wound healing, and Transwell assays were carried out to evaluate the effects of SPP1 and BET inhibitors in melanoma cells in vitro. A xenograft mouse model was used to investigate the effect of SPP1 and BET inhibitors on melanoma in vivo. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the regulatory mechanism of BET inhibitors on SPP1. Results: SPP1 was identified as a melanoma driver by bioinformatics analysis, and meta-analysis determined it to be a diagnostic and prognostic biomarker for melanoma. SPP1 overexpression was associated with poor melanoma prognosis, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion. Through a pilot drug screen, we identified BET inhibitors as ideal therapeutic agents that suppressed SPP1 expression. Also, SPP1 overexpression could partially reverse the suppressive effect of BET inhibitors on melanoma. We further demonstrated that bromodomain-containing 4 (BRD4) regulated SPP1 expression. Notably, BRD4 did not bind directly to the SPP1 promoter but regulated SPP1 expression through NFKB2. Silencing of NFKB2 resembled the phenotype of BET inhibitors treatment and SPP1 silencing in melanoma. Conclusion: Our findings highlight SPP1 as an essential target of BET inhibitors and provide a novel mechanism by which BET inhibitors suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway. Ivyspring International Publisher 2020-09-15 /pmc/articles/PMC7546000/ /pubmed/33052224 http://dx.doi.org/10.7150/thno.47432 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Deng, Guangtong
Zeng, Furong
Su, Juan
Zhao, Shuang
Hu, Rui
Zhu, Wu
Hu, Shuo
Chen, Xiang
Yin, Mingzhu
BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway
title BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway
title_full BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway
title_fullStr BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway
title_full_unstemmed BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway
title_short BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway
title_sort bet inhibitor suppresses melanoma progression via the noncanonical nf-κb/spp1 pathway
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546000/
https://www.ncbi.nlm.nih.gov/pubmed/33052224
http://dx.doi.org/10.7150/thno.47432
work_keys_str_mv AT dengguangtong betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT zengfurong betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT sujuan betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT zhaoshuang betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT hurui betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT zhuwu betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT hushuo betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT chenxiang betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway
AT yinmingzhu betinhibitorsuppressesmelanomaprogressionviathenoncanonicalnfkbspp1pathway