The DNA Damage Transducer RNF8 Facilitates Cancer Chemoresistance and Progression through Twist Activation

Lee, H. J., Li, C. F., Ruan, D., Powers, S., Thompson, P. A., Frohman, M. A., Chan, C. H. (September 2016) The DNA Damage Transducer RNF8 Facilitates Cancer Chemoresistance and Progression through Twist Activation. Mol Cell, 63 (6). pp. 1021-33. ISSN 1097-2765

DOI: 10.1016/j.molcel.2016.08.009


Twist has been shown to cause treatment failure, cancer progression, and cancer-related death. However, strategies that directly target Twist are not yet conceivable. Here we reveal that K63-linked ubiquitination is a crucial regulatory mechanism for Twist activation. Through an E3 ligase screen and biochemical studies, we unexpectedly identified that RNF8 functions as a direct Twist activator by triggering K63-linked ubiquitination of Twist. RNF8-promoted Twist ubiquitination is required for Twist localization to the nucleus for subsequent EMT and CSC functions, thereby conferring chemoresistance. Our histological analyses showed that RNF8 expression is upregulated and correlated with disease progression, EMT features, and poor patient survival in breast cancer. Moreover, RNF8 regulates cancer cell migration and invasion and cancer metastasis, recapitulating the effect of Twist. Together, our findings reveal a previously unrecognized tumor-promoting function of RNF8 and provide evidence that targeting RNF8 is an appealing strategy to tackle tumor aggressiveness and treatment resistance.

Item Type: Paper
Uncontrolled Keywords: Animals Antineoplastic Agents/therapeutic use Breast Neoplasms/drug therapy/*genetics/mortality/pathology Cell Line, Tumor DNA Damage DNA-Binding Proteins/antagonists & inhibitors/*genetics/metabolism Disease Progression Drug Resistance, Neoplasm/*genetics Epithelial-Mesenchymal Transition Female *Gene Expression Regulation, Neoplastic Genes, Reporter Humans Luciferases/genetics/metabolism Lysine/metabolism MCF-7 Cells Mice, Nude Neoplasm Invasiveness Neoplasm Transplantation Neoplastic Stem Cells/drug effects/*metabolism/pathology Nuclear Proteins/antagonists & inhibitors/*genetics/metabolism RNA, Small Interfering/genetics/metabolism Signal Transduction Survival Analysis Twist-Related Protein 1/antagonists & inhibitors/*genetics/metabolism Ubiquitination
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies > chemoresistance
diseases & disorders > cancer > drugs and therapies
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL labs > Powers lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
Depositing User: Matt Covey
Date: 15 September 2016
Date Deposited: 06 Mar 2018 21:13
Last Modified: 05 Nov 2020 20:54
PMCID: PMC5026628
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