Lee Hong-Jen, Li Chien-Feng, Ruan Diane, Powers Scott, Thompson Patricia A, Frohman Michael A, Chan Chia-Hsin
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan.
Mol Cell. 2016 Sep 15;63(6):1021-33. doi: 10.1016/j.molcel.2016.08.009. Epub 2016 Sep 8.
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.
Twist已被证明会导致治疗失败、癌症进展和癌症相关死亡。然而，直接靶向Twist的策略目前还难以想象。在此我们揭示，K63连接的泛素化是Twist激活的关键调控机制。通过E3连接酶筛选和生化研究，我们意外发现RNF8通过触发Twist的K63连接泛素化而作为直接的Twist激活因子发挥作用。RNF8促进的Twist泛素化是Twist定位于细胞核以实现随后的上皮-间质转化（EMT）和癌症干细胞（CSC）功能所必需的，从而赋予化学抗性。我们的组织学分析表明，在乳腺癌中，RNF8表达上调且与疾病进展、EMT特征以及患者不良生存相关。此外，RNF8调节癌细胞迁移、侵袭和癌症转移，重现了Twist的作用。总之，我们的研究结果揭示了RNF8此前未被认识到的促肿瘤功能，并提供证据表明靶向RNF8是应对肿瘤侵袭性和治疗抗性的一种有吸引力的策略。
