HACE1 Prevents Lung Carcinogenesis via Inhibition of RAC-Family GTPases.

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.