Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna BioCentre, Vienna, Austria.
Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Switzerland.
Cancer Res. 2020 Jul 15;80(14):3009-3022. doi: 10.1158/0008-5472.CAN-19-2270. Epub 2020 May 4.
HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here, we report that is frequently mutated in human lung cancer. In mice, loss of led to enhanced progression of -driven lung tumors. Additional ablation of the oncogenic GTPase partially reduced progression of lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in -deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both and fully averted the increased progression of -driven lung tumors in mice. In patients with lung cancer, increased expression of correlated with reduced levels of and and prolonged survival, whereas elevated expression of and was associated with poor prognosis. This work defines HACE1 as a crucial regulator of the oncogenic activity of RAC-family GTPases in lung cancer development. SIGNIFICANCE: These findings reveal that mutation of the tumor suppressor HACE1 disrupts its role as a regulator of the oncogenic activity of RAC-family GTPases in human and murine lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/14/3009/F1.large.jpg.
HACE1 是一种 E3 泛素连接酶，在肿瘤生物学和组织稳态中具有重要作用。已经发现 的缺失或突变与多种肿瘤的发生有关，但潜在的机制尚未确定。在这里，我们报告 在人类肺癌中经常发生突变。在小鼠中， 的缺失导致由 驱动的肺肿瘤的进展增强。另外，致癌 GTPase 的缺失部分减少了 驱动的肺肿瘤的进展。HACE1 的新型泛素化靶标 RAC2 可以补偿其同源物 RAC1 在 缺陷型肿瘤中，但不能在 HACE1 充足型肿瘤中的缺失。因此， 和 的同时缺失完全阻止了 驱动的肺肿瘤在 小鼠中的进展增加。在肺癌患者中， 的表达增加与 和 水平降低以及生存时间延长相关，而 和 的表达升高与预后不良相关。这项工作定义了 HACE1 作为 RAC 家族 GTPase 致癌活性在肺癌发展中的关键调节剂。意义：这些发现揭示了肿瘤抑制因子 HACE1 的突变破坏了它作为人类和鼠类肺癌中 RAC 家族 GTPase 致癌活性的调节剂的作用。
