title: E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation.
abstract: To identify novel oncogenic E3 ubiquitin ligases as anticancer targets, we screened an E3 ubiquitin ligase siRNA library containing siRNA pools against 555 individual E3s using the sulphorhodamine B assay in the MDA-MB-231 breast cancer cell line and the PC3 prostate cancer cell line. RNF126 was identified and validated as a candidate from this screening. Knockdown of RNF126 dramatically decreased cell viability in these cancer cell lines. Consistently, RNF126 knockdown delayed cell-cycle G(1)-S progression and decreased cell proliferation. Using protein array analysis we found that RNF126 silencing increased cell-cycle dependent kinase inhibitor p21(cip) protein levels in both MDA-MB-231 and PC3. Knockdown of RNF126 stabilized the p21 protein rather than increased p21 mRNA levels. We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. RNF126 knockdown induced loss of cell viability in MDA-MB-231 and PC-3 can be partially rescued by depletion of p21. RNF126 stable knockdown in PC3 inhibited tumor growth in SCID mice. Finally, we found that RNF126 is highly expressed in a subset of breast cancer cell lines and negatively correlated with p21 expression levels. These findings suggest that RNF126 promotes cancer cell proliferation by targeting p21 for ubiquitin-mediated degradation. RNF126 could be a novel therapeutic target in breast and prostate cancers.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhi
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.forename: Zehua
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: Zhou
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Wenlin
authors.initials: W
authors.lastname: Chen
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Ceshi
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism*; D040081:Protein Array Analysis; D014183:Transplantation, Heterologous; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases