HACE1 prevents lung carcinogenesis via inhibition of RAC-Family GTPases

Melanie Kogler, Luigi Tortola, Gian Luca Negri, Alexandra Leopoldi, Amal M. El-Naggar, Stefan Mereiter, Carlos Gomez-Diaz, Roberto Nitsch, Davide Tortora, Anoop M. Kavirayani, Bianca V. Gapp, Shuan Rao, Iris Uribesalgo, David Hoffmann, Domagoj Cikes, Maria Novatchkova, David A. Williams, Jeffrey M. Trent, Fumiyo Ikeda, Mads DaugaardAstrid Hagelkruys, Poul H. Sorensen, Josef M. Penninger

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


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 patients with lung cancer, increased expression of HACE1 correlated with reduced levels of RAC1 and RAC2 and prolonged survival, whereas 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.

Original languageEnglish
Pages (from-to)3009-3022
Number of pages14
JournalCancer Research
Issue number14
Publication statusPublished - Jul 15 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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