HACE1 Prevents Lung Carcinogenesis via Inhibition of RAC-Family GTPases.
HACE1 Prevents Lung Carcinogenesis via Inhibition of RAC-Family GTPases.
复制标题
DOI：
10.1158/0008-5472.can-19-2270
复制
发表时间：
2020-07-15
期刊：
影响因子：
11.2
通讯作者：
Penninger JM
中科院分区：
文献类型：
--
作者：
Kogler M;Tortola L;Negri GL;Leopoldi A;El-Naggar AM;Mereiter S;Gomez-Diaz C;Nitsch R;Tortora D;Kavirayani AM;Gapp BV;Rao S;Uribesalgo I;Hoffmann D;Cikes D;Novatchkova M;Williams DA;Trent JM;Ikeda F;Daugaard M;Hagelkruys A;Sorensen PH;Penninger JM
HACE1是一种E3泛素连接酶，在肿瘤生物学和组织动态平衡中具有重要作用。HACE1的缺失或突变与多种肿瘤的发生有关，但其潜在的机制尚未明确。在此，我们报告了HACE1在人类肺癌中的频繁突变。在小鼠中，Hace1的缺失导致了KrasG12D驱动的肺癌的加速进展。另外，切除致癌的GTPase rac1部分减缓了Hace1-/-肺肿瘤的进展。RAC2是HACE1的一个新的泛素化靶点，在HACE1缺失的肿瘤中可以弥补其同源基因RAC1的缺失，但在HACE1缺失的肿瘤中则不能。因此，在Hace1/-小鼠中，切除rac1和rac2完全避免了KrasG12D驱动的肺癌进展的增加。在肺癌患者中，HACE1的高表达与RAC1和RAC2水平的降低以及生存期的延长相关，而RAC1和RAC2的高表达与预后不良相关。这项工作将HACE1定义为肺癌发生过程中RAC家族GTP酶致癌活性的关键调节因子。
HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of HACE1 has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here we report that HACE1 is frequently mutated in human lung cancer. In mice, loss of Hace1 led to enhanced progression of KRasG12D-driven lung tumors. Additional ablation of the oncogenic GTPase Rac1 partially reduced progression of Hace1-/- lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in Hace1-deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both Rac1 and Rac2 fully averted the increased progression of KRasG12D-driven lung tumors in Hace1-/- mice. In lung cancer patients, increased expression of HACE1 correlated with reduced levels of RAC1 and RAC2 and prolonged survival, while elevated expression of RAC1 and RAC2 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.