TY - JOUR
T1 - HACE1 prevents lung carcinogenesis via inhibition of RAC-Family GTPases
AU - Kogler, Melanie
AU - Tortola, Luigi
AU - Negri, Gian Luca
AU - Leopoldi, Alexandra
AU - El-Naggar, Amal M.
AU - Mereiter, Stefan
AU - Gomez-Diaz, Carlos
AU - Nitsch, Roberto
AU - Tortora, Davide
AU - Kavirayani, Anoop M.
AU - Gapp, Bianca V.
AU - Rao, Shuan
AU - Uribesalgo, Iris
AU - Hoffmann, David
AU - Cikes, Domagoj
AU - Novatchkova, Maria
AU - Williams, David A.
AU - Trent, Jeffrey M.
AU - Ikeda, Fumiyo
AU - Daugaard, Mads
AU - Hagelkruys, Astrid
AU - Sorensen, Poul H.
AU - Penninger, Josef M.
N1 - Funding Information:
D.A. Williams disclosed commercial research funding from Bluebird Bio and Novartis. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-2270
DO - 10.1158/0008-5472.CAN-19-2270
M3 - Article
C2 - 32366477
AN - SCOPUS:85088156116
SN - 0008-5472
VL - 80
SP - 3009
EP - 3022
JO - Cancer Research
JF - Cancer Research
IS - 14
ER -
