TY - JOUR
T1 - A novel signature of ccnf-associated e3 ligases collaborate and counter each other in breast cancer
AU - Chang, Shu Chun
AU - Hung, Chin Sheng
AU - Zhang, Bo Xiang
AU - Hsieh, Tsung Han
AU - Hsu, Wayne
AU - Ding, Jeak Ling
N1 - Funding Information:
Author Contributions: Conceptualization, S.-C.C. and J.L.D.; methodology, S.-C.C. and B.-X.Z.; software, T.-H.H.; validation, S.-C.C., C.-S.H., B.-X.Z. and W.H.; formal analysis, S.-C.C.; investigation, S.-C.C. and B.-X.Z.; resources, C.-S.H. and W.H.; data curation, S.-C.C. and C.-S.H.; writing— original draft preparation, S.-C.C.; writing—review and editing, J.L.D.; visualization, S.-C.C.; supervision, S.-C.C.; project administration, S.-C.C.; funding acquisition, S.-C.C., C.-S.H. and W.H. All authors have read and agreed to the published version of the manuscript Funding: This work was jointly supported by the Ministry of Science and Technology, Taiwan (MOST109-2314-B-038-087); Taipei Medical University (106TMU-TMUH-15); the Ministry of Education, Singapore (R-154-000-A76-114 and R-154-000-C43-281).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/6/2
Y1 - 2021/6/2
N2 - 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 ubiq-uitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregu-lation of four SCFF-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, sug-gesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, in-dicating 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 overexpres-sion 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.
AB - 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 ubiq-uitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregu-lation of four SCFF-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, sug-gesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, in-dicating 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 overexpres-sion 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.
KW - Breast cancer
KW - CCNF
KW - E3 ubiquitin ligase
KW - FBXL8
KW - FZR1
KW - Metastasis
KW - RRM2
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U2 - 10.3390/cancers13122873
DO - 10.3390/cancers13122873
M3 - Article
AN - SCOPUS:85107367544
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 12
M1 - 2873
ER -