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RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2
- Source :
- Cell Death Differ
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Deregulation of E3 ubiquitin ligases is intimately implicated in breast cancer pathogenesis and progression, but the underlying mechanisms still remain elusive. Here we report that RING finger protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, functions as a tumor suppressor in breast cancer. RNF144A was downregulated in a subset of primary breast tumors and restoration of RNF144A suppressed breast cancer cell proliferation, colony formation, migration, invasion in vitro, tumor growth, and lung metastasis in vivo. In contrast, knockdown of RNF144A promoted malignant phenotypes of breast cancer cells. Quantitative proteomics and biochemical analysis revealed that RNF144A interacted with and targeted heat-shock protein family A member 2 (HSPA2), a putative oncoprotein that is frequently upregulated in human cancer and promotes tumor growth and progression, for ubiquitination and degradation. Notably, the ligase activity-defective mutants of RNF144A impaired its ability to induce ubiquitination and degradation of HSPA2, and to suppress breast cancer cell proliferation, migration, and invasion as compared with its wild-type counterpart. Moreover, RNF144A-mediated suppression of breast cancer cell proliferation, migration, and invasion was rescued by ectopic HSPA2 expression. Clinically, low RNF144A and high HSPA2 expression in breast cancer patients was correlated with aggressive clinicopathological characteristics and decreased overall and disease-free survival. Collectively, these findings reveal a previously unappreciated role for RNF144A in suppression of breast cancer growth and metastasis, and identify RNF144A as the first, to our knowledge, E3 ubiquitin ligase for HSPA2 in human cancer.
- Subjects :
- 0301 basic medicine
Proteasome Endopeptidase Complex
Lung Neoplasms
Ubiquitin-Protein Ligases
Down-Regulation
Mice, Nude
Breast Neoplasms
Models, Biological
Article
Metastasis
03 medical and health sciences
0302 clinical medicine
Breast cancer
Downregulation and upregulation
Ubiquitin
Cell Movement
Cell Line, Tumor
HSPA2
medicine
Animals
Humans
HSP70 Heat-Shock Proteins
Neoplasm Invasiveness
Molecular Biology
Cell Proliferation
Mice, Inbred BALB C
Gene knockdown
biology
Protein Stability
Cell growth
Tumor Suppressor Proteins
Ubiquitination
Oncogenes
Cell Biology
Prognosis
medicine.disease
Xenograft Model Antitumor Assays
Ubiquitin ligase
030104 developmental biology
030220 oncology & carcinogenesis
Proteolysis
biology.protein
Cancer research
Female
Carrier Proteins
Subjects
Details
- ISSN :
- 14765403 and 13509047
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Cell Death & Differentiation
- Accession number :
- edsair.doi.dedup.....321dd8f30ac3797fac527c3139383a49