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

• Published in: Molecular cell 2016-09, Vol.63 (6), p.1021-1033
• Main Authors: Lee, Hong-Jen, Li, Chien-Feng, Ruan, Diane, Powers, Scott, Thompson, Patricia A., Frohman, Michael A., Chan, Chia-Hsin
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Line, Tumor; Disease Progression; DNA Damage; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Luciferases - genetics; Luciferases - metabolism; Lysine - metabolism; MCF-7 Cells; Mice, Nude; Neoplasm Invasiveness; Neoplasm Transplantation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Survival Analysis; Twist-Related Protein 1 - antagonists & inhibitors; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Ubiquitination
• ISSN: 1097-2765; 1097-4164
• 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. [Display omitted] •K63-linked ubiquitination activates Twist and EMT•RNF8 activates EMT and CSC self-renewal via Twist K63-linked ubiquitination•RNF8 overexpression in breast cancer predicts poor disease outcomes•RNF8 deficiency inhibits CSC self-renewal and cancer metastasis RNF8 is known as a genome guardian. Lee et al. employed an E3 ligase screen, revealing RNF8 as an activator of Twist and cancer. RNF8 regulates cancer metastasis, and its overexpression is correlated with poor disease outcomes, opening up a new perspective on the cancer-promoting actions of DNA damage regulators.