Department of Oncology, University of Oxford, Oxford, UK.
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
EMBO Rep. 2022 Feb 3;23(2):e51287. doi: 10.15252/embr.202051287. Epub 2021 Dec 13.
RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of γ-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors.
RASSF1A 启动子甲基化与肿瘤去分化和侵袭性致癌行为相关。然而，RASSF1A 依赖性肿瘤去分化的潜在机制仍不清楚。在这里，我们表明 RASSF1A 可直接解偶联 NOTCH-HES1 轴，该轴是分化的关键抑制物。有趣的是，RASSF1A 与 HES1 的串扰与连接 RASSF1A 与 Hippo 途径的信号通路无关。在分子水平上，我们证明 RASSF1A 作为一个支架，对于 SUMO 靶向的 E3 连接酶 SNURF/RNF4 靶向 HES1 降解是必需的。RASSF1A 和 HES1 之间的这种相互关系在广泛的人类肿瘤中都很明显，突出了所鉴定途径的临床意义。我们表明，在 RASSF1A 耗尽的环境中 HES1 的上调使细胞对 γ-分泌酶抑制剂（GSIs）的下游效应不敏感，GSIs 可在 NOTCH 受体水平上限制信号传导。总之，我们报告了一种机制，通过该机制，RASSF1A 对关键的 Notch 效应物 HES1 进行自主调节，从而将 RASSF1A 的表达归类为 Notch 抑制剂临床疗效的整体决定因素。
