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Open AccessArticle

Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors

by Shu-Chun Chang 1,†, Wayne Hsu 2, Emily Chia-Yu Su 3,4, Chin-Sheng Hung 5,6,7,* and Jeak Ling Ding 8,9,*,†
1
The Ph.D. Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
2
Division of Acute Care Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan
3
Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
4
Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
5
Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan
6
Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan
7
Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
8
Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
9
Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore
*
Authors to whom correspondence should be addressed.
Co-senior authors: The PhD Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University (S.-C.C.); Department of Biological Sciences, National University of Singapore (J.L.D.).
Cancers 2020, 12(8), 2210; https://doi.org/10.3390/cancers12082210
Received: 9 July 2020 / Revised: 31 July 2020 / Accepted: 5 August 2020 / Published: 7 August 2020
(This article belongs to the Special Issue Ubiquitin-Related Cancer)
The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics. View Full-Text
Keywords: FBXL8 SCF E3 ubiquitin ligase; CCND2; IRF5; breast cancer (BRCA) and metastasis; pro-tumorigenic microenvironment FBXL8 SCF E3 ubiquitin ligase; CCND2; IRF5; breast cancer (BRCA) and metastasis; pro-tumorigenic microenvironment
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MDPI and ACS Style

Chang, S.-C.; Hsu, W.; Su, E. .-Y.; Hung, C.-S.; Ding, J.L. Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors. Cancers 2020, 12, 2210.

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