Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
Cell Death Dis. 2020 Oct 17;11(10):873. doi: 10.1038/s41419-020-03081-w.
The HER2-positive breast cancer subtype (HER2-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment strategies. Epigenetic regulators are commonly misregulated in cancer and represent attractive molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by the heterodimeric ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2-BC. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin-cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2-BC, revealing the H2B monoubiquitination axis as a possible tumor context-dependent therapeutic target in breast cancer.
人表皮生长因子受体 2（HER2）阳性乳腺癌（HER2-BC）具有特别侵袭性的生物学行为。抗 HER2 治疗显著改善了 HER2-BC 患者的生存。然而，大量患者对当前的靶向治疗产生耐药，需要开发新的治疗策略。在癌症中，表观遗传调节剂通常失调，是有吸引力的分子治疗靶点。异二聚体泛素连接酶复合物 RNF20/RNF40 对组蛋白 H2B 的单泛素化（H2Bub1）已被描述具有肿瘤抑制功能，并且 H2Bub1 的缺失与癌症进展有关。在这项研究中，我们利用人肿瘤样本、细胞培养模型和组织特异性 Rnf40 缺失的乳腺肿瘤小鼠模型，确定了 RNF40 在 HER2-BC 中的出乎意料的肿瘤支持作用。我们证明，RNF40 驱动的 H2B 单泛素化对于 RHO/ROCK/LIMK 途径成分的转录激活以及通过与组蛋白 3 赖氨酸 4 三甲基化（H3K4me3）的跨组蛋白串扰的适当肌动蛋白细胞骨架动力学是必需的。总的来说，这项工作证明了 RNF40 在 HER2-BC 中的先前未知的重要作用，揭示了 H2B 单泛素化轴作为乳腺癌中可能的肿瘤上下文相关治疗靶点。
