HACE1 Prevents Lung Carcinogenesis via Inhibition of RAC-Family GTPases

Abstract

HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of <i>HACE1</i> has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here, we report that <i>HACE1</i> is frequently mutated in human lung cancer. In mice, loss of <i>Hace1</i> led to enhanced progression of <i>KRas^G12D</i> -driven lung tumors. Additional ablation of the oncogenic GTPase <i>Rac1</i> partially reduced progression of <i>Hace1^-/-</i> lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in <i>Hace1</i>-deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both <i>Rac1</i> and <i>Rac2</i> fully averted the increased progression of <i>KRas^G12D</i> -driven lung tumors in <i>Hace1^-/-</i> mice. In patients with lung cancer, increased expression of <i>HACE1</i> correlated with reduced levels of <i>RAC1</i> and <i>RAC2</i> and prolonged survival, whereas elevated expression of <i>RAC1</i> and <i>RAC2</i> 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.