TY - JOUR
T1 - Inhibitor of differentiation-1 sustains mutant KRAS-driven progression, maintenance, and metastasis of lung adenocarcinoma via regulation of a FOSL1 network
AU - Román, Marta
AU - López, Inés
AU - Guruceaga, Elisabeth
AU - Baraibar, Iosune
AU - Ecay, Margarita
AU - Collantes, María
AU - Nadal, Ernest
AU - Vallejo, Adrian
AU - Cadenas, Silvia
AU - Miguel, Marta Echavarride
AU - Jang, Jae Hwi
AU - Martin-Uriz, Patxi San
AU - Castro-Labrador, Laura
AU - Vilas-Zornoza, Amaia
AU - Lara-Astiaso, David
AU - Ponz-Sarvise, Mariano
AU - Rolfo, Christian
AU - Santos, Edgardo S.
AU - Raez, Luis E.
AU - Taverna, Simona
AU - Behrens, Carmen
AU - Weder, Walter
AU - Wistuba, Ignacio I.
AU - Vicent, Silvestre
AU - Gil-Bazo, Ignacio
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G 2 -M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in down-regulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD.
AB - Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G 2 -M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in down-regulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD.
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U2 - 10.1158/0008-5472.CAN-18-1479
DO - 10.1158/0008-5472.CAN-18-1479
M3 - Article
C2 - 30563891
AN - SCOPUS:85060956600
SN - 0008-5472
VL - 79
SP - 625
EP - 638
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -