The DNA Damage Transducer RNF8 Facilitates Cancer Chemoresistance and Progression through Twist Activation.
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.
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
Hong-Jen
HJ
Lee
National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan.
Chien-Feng
CF
Li
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
Diane
D
Ruan
Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
Scott
S
Powers
Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
Patricia A
PA
Thompson
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
Michael A
MA
Frohman
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: chia-hsin.chan@stonybrook.edu.
Chia-Hsin
CH
Chan
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C486521:RNF8 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D008156:Luciferases; D044767:Ubiquitin-Protein Ligases; D008239:Lysine