Dataset Information

Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3.

ABSTRACT: CRL4, a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in ovarian cancers. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. Here, we show that CRL4 is considerably increased in cisplatin-resistant ovarian cancer cells, and CRL4 knockdown with shRNAs is able to reverse cisplatin-resistance of ovarian cancer cells. Moreover, CRL4 knockdown markedly inhibits the expression of BIRC3, one of the inhibitors of apoptosis proteins (IAPs). Besides, lower expression level of BIRC3 is associated with better prognosis of ovarian cancer patients, and BIRC3 knockdown in ovarian cancer cells can recover their sensitivity to cisplatin. More importantly, we demonstrate that CRL4 regulates BIRC3 expression by mediating the STAT3, but not the PI3K pathway. Therefore, our results identified CRL4 as an important factor in ovarian cancer chemoresistance, suggesting that CRL4 and BIRC3 may serve as novel therapeutic targets for relapsed patients after treatment with cisplatin and its derivative to overcome the bottle neck of ovarian cancer chemoresistance.

SUBMITTER: Hu X

PROVIDER: S-EPMC6362125 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3.

Hu Xiaoyan X Meng Yang Y Xu Lian L Qiu Lei L Wei Mingtian M Su Dan D Qi Xu X Wang Ziqiang Z Yang Shengyong S Liu Cong C Han Junhong J

Cell death & disease 20190204 2

CRL4, a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in ovarian cancers. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. Here, we show that CRL4 is considerably increased in cisplatin-resistant ovarian cancer cells, and CRL4 knockdown with shRNAs is able to reverse cisplatin-resistance of ovarian cancer cells. Moreover, CRL4 knockdown markedly inhibits ...[more]

PMID: 30718461

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Project description:CCAAT/enhancer-binding protein alpha (C/EBP?) is an important transcription factor involved in granulocytic differentiation. Here, for the first time we demonstrate that E6-associated protein (E6AP), an E3 ubiquitin ligase targets C/EBP? for ubiquitin-mediated proteasome degradation and thereby negatively modulates its functions. Wild-type E6AP promotes ubiquitin dependent proteasome degradation of C/EBP?, while catalytically inactive E6-associated protein having cysteine replaced with alanine at amino-acid position 843 (E6AP-C843A) rather stabilizes it. Further, these two proteins physically associate both in non-myeloid (overexpressed human embryonic kidney epithelium) and myeloid cells. We show that E6AP-mediated degradation of C/EBP? protein expression curtails its transactivation potential on its target genes. Noticeably, E6AP degrades both wild-type 42?kDa CCAAT-enhancer-binding protein alpha (p42C/EBP?) and mutant isoform 30?kDa CCAAT-enhancer-binding protein alpha (p30C/EBP?), this may explain perturbed p42C/EBP?/p30C/EBP? ratio often observed in acute myeloid leukemia (AML). We show that overexpression of catalytically inactive E6AP-C843A in C/EBP? inducible K562- p42C/EBP?-estrogen receptor (ER) cells inhibits ?-estradiol (E2)-induced C/EBP? degradation leading to enhanced granulocytic differentiation. This enhanced granulocytic differentiation upon E2-induced activation of C/EBP? in C/EBP? stably transfected cells (?-estradiol inducible K562 cells stably expressing p42C/EBP?-ER (K562-C/EBP?-p42-ER)) was further substantiated by siE6AP-mediated knockdown of E6AP in both K562-C/EBP?-p42-ER and 32dcl3 (32D clone 3, a cell line widely used model for in vitro study of hematopoietic cell proliferation, differentiation, and apoptosis) cells. Taken together, our data suggest that E6AP targeted C/EBP? protein degradation may provide a possible explanation for both loss of expression and/or functional inactivation of C/EBP? often experienced in myeloid leukemia.

Dataset Information

Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3.

Publications

Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3.

Similar Datasets

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