Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States.
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States.
Cell Signal. 2020 Jun;70:109574. doi: 10.1016/j.cellsig.2020.109574. Epub 2020 Feb 19.
KLF4 plays an important role in orchestrating a variety of cellular events, including cell-fate decision, genome stability and apoptosis. Its deregulation is correlated with human diseases such as breast cancer and gastrointestinal cancer. Results from recent biochemical studies have revealed that KLF4 is tightly regulated by posttranslational modifications. Here we report a new finding that KLF4 orchestrates estrogen receptor signaling and facilitates endocrine resistance. We also uncovered the underlying mechanism that alteration of KLF4 by posttranslational modifications such as phosphorylation and ubiquitylation changes tumor cell response to endocrine therapy drugs. IHC analyses using based on human breast cancer specimens showed the accumulation of KLF4 protein in ER-positive breast cancer tissues. Elevated KLF4 expression significantly correlated with prognosis and endocrine resistance. Our drug screening for suppressing KLF4 protein expression led to identification of Src kinase to be a critical player in modulating KLF4-mediated tamoxifen resistance. Depletion of VHL (von Hippel-Lindau tumor suppressor), a ubiquitin E3 ligase for KLF4, reduces tumor cell sensitivity to tamoxifen. We demonstrated phosphorylation of VHL by Src enhances proteolysis of VHL that in turn leads to upregulation of KLF4 and increases endocrine resistance. Suppression of Src-VHL-KLF4 cascade by Src inhibitor or enhancement of VHL-KLF4 ubiquitination by TAT-KLF4 (371-420AAa) peptides re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen treatment. Taken together, our findings demonstrate a novel role for KLF4 in modulating endocrine resistance via the Src-VHL-KLF4 axis.
KLF4 在协调多种细胞事件中发挥着重要作用，包括细胞命运决定、基因组稳定性和细胞凋亡。其失调与乳腺癌和胃肠道癌等人类疾病有关。最近的生化研究结果表明，KLF4 受到翻译后修饰的严格调控。在这里，我们报告了一个新的发现，即 KLF4 协调雌激素受体信号转导并促进内分泌抵抗。我们还揭示了 KLF4 通过翻译后修饰（如磷酸化和泛素化）改变肿瘤细胞对内分泌治疗药物反应的潜在机制。使用基于人类乳腺癌标本的 IHC 分析显示，KLF4 蛋白在 ER 阳性乳腺癌组织中积累。KLF4 表达水平升高与预后和内分泌抵抗显著相关。我们抑制 KLF4 蛋白表达的药物筛选导致鉴定出 Src 激酶是调节 KLF4 介导的他莫昔芬耐药的关键因素。VHL（von Hippel-Lindau 肿瘤抑制因子）的消耗，一种 KLF4 的泛素 E3 连接酶，降低了肿瘤细胞对他莫昔芬的敏感性。我们证明 Src 通过磷酸化 VHL 增强 VHL 的蛋白水解，进而导致 KLF4 的上调，并增加内分泌抵抗。通过 Src 抑制剂抑制 Src-VHL-KLF4 级联反应或通过 TAT-KLF4（371-420AAa）肽增强 VHL-KLF4 泛素化可使他莫昔芬耐药的乳腺癌细胞重新对他莫昔芬治疗敏感。总之，我们的研究结果表明，KLF4 通过 Src-VHL-KLF4 轴在调节内分泌抵抗中发挥着新的作用。
