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A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer

SIMPLE SUMMARY: The dysregulation of UPS exacerbates the tumor microenvironment and drives malignant transformation. As the largest family of E3 ligases, the SCF(F-boxes) promotes BRCA progression. FBXL8 was recently identified to be a novel SCF E3 ligase that potently promotes BRCA. Here, we profil...

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Autores principales: Chang, Shu-Chun, Hung, Chin-Sheng, Zhang, Bo-Xiang, Hsieh, Tsung-Han, Hsu, Wayne, Ding, Jeak Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228695/
https://www.ncbi.nlm.nih.gov/pubmed/34201347
http://dx.doi.org/10.3390/cancers13122873
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author Chang, Shu-Chun
Hung, Chin-Sheng
Zhang, Bo-Xiang
Hsieh, Tsung-Han
Hsu, Wayne
Ding, Jeak Ling
author_facet Chang, Shu-Chun
Hung, Chin-Sheng
Zhang, Bo-Xiang
Hsieh, Tsung-Han
Hsu, Wayne
Ding, Jeak Ling
author_sort Chang, Shu-Chun
collection PubMed
description SIMPLE SUMMARY: The dysregulation of UPS exacerbates the tumor microenvironment and drives malignant transformation. As the largest family of E3 ligases, the SCF(F-boxes) promotes BRCA progression. FBXL8 was recently identified to be a novel SCF E3 ligase that potently promotes BRCA. Here, we profiled the transcriptome of BRCA patient tissues by global NGS RNA-Seq and TCGA database analyses. A signature of four SCF(F-box) E3 ligases (FBXL8, FBXO43, FBXO15, CCNF) was found to be pivotal for BRCA advancement. Knockdown of FBXL8 and FBXO43 reduced cancer cell viability and proliferation, suggesting their pro-tumorigenic roles. However, the overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. FBXL8 and FZR1 pulled down CCNF, and double knockdown of FBXL8 and FZR1 caused CCNF accumulation. Additionally, CCNF partnered with a pro-tumorigenic factor, RRM2, and overexpression of CCNF reduced RRM2. Our findings suggest a potential for drugging CCNF in co-modulatory partnership with FBXL8 and FZR1, for anti-BRCA therapy. ABSTRACT: Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCF(F-boxes)) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCF(F-boxes) is a key component of E3 ligases, we hypothesized that other SCF(F-boxes) besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCF(F-box) E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression.
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spelling pubmed-82286952021-06-26 A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer Chang, Shu-Chun Hung, Chin-Sheng Zhang, Bo-Xiang Hsieh, Tsung-Han Hsu, Wayne Ding, Jeak Ling Cancers (Basel) Article SIMPLE SUMMARY: The dysregulation of UPS exacerbates the tumor microenvironment and drives malignant transformation. As the largest family of E3 ligases, the SCF(F-boxes) promotes BRCA progression. FBXL8 was recently identified to be a novel SCF E3 ligase that potently promotes BRCA. Here, we profiled the transcriptome of BRCA patient tissues by global NGS RNA-Seq and TCGA database analyses. A signature of four SCF(F-box) E3 ligases (FBXL8, FBXO43, FBXO15, CCNF) was found to be pivotal for BRCA advancement. Knockdown of FBXL8 and FBXO43 reduced cancer cell viability and proliferation, suggesting their pro-tumorigenic roles. However, the overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. FBXL8 and FZR1 pulled down CCNF, and double knockdown of FBXL8 and FZR1 caused CCNF accumulation. Additionally, CCNF partnered with a pro-tumorigenic factor, RRM2, and overexpression of CCNF reduced RRM2. Our findings suggest a potential for drugging CCNF in co-modulatory partnership with FBXL8 and FZR1, for anti-BRCA therapy. ABSTRACT: Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCF(F-boxes)) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCF(F-boxes) is a key component of E3 ligases, we hypothesized that other SCF(F-boxes) besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCF(F-box) E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression. MDPI 2021-06-08 /pmc/articles/PMC8228695/ /pubmed/34201347 http://dx.doi.org/10.3390/cancers13122873 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chang, Shu-Chun
Hung, Chin-Sheng
Zhang, Bo-Xiang
Hsieh, Tsung-Han
Hsu, Wayne
Ding, Jeak Ling
A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer
title A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer
title_full A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer
title_fullStr A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer
title_full_unstemmed A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer
title_short A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer
title_sort novel signature of ccnf-associated e3 ligases collaborate and counter each other in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228695/
https://www.ncbi.nlm.nih.gov/pubmed/34201347
http://dx.doi.org/10.3390/cancers13122873
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