Abstract
ECT2 mediates Kras-Trp53–driven lung adenocarcinoma initiation and transformed growth.
Major finding: ECT2 mediates Kras-Trp53–driven lung adenocarcinoma initiation and transformed growth.
Mechanism: PKCι promotes the ECT2–UBF1 interaction to drive rDNA transcription and transformation via RAC1 and NPM.
Impact: The PKCι–ECT2–UBF1–RAC1–NPM signaling axis is a potential therapeutic target for mutant KRAS lung tumors.
The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (ECT2), which activates RHO GTPases to regulate cytokinesis, is localized to the nucleus in its inactive form during interphase and is present in the cytoplasm during mitosis. Recently, it has been shown that both nuclear and cytoplasmic ECT2 are elevated in several tumor types, including non–small cell lung cancer (NSCLC). Having shown that ECT2 mediates PKCι-regulated RAC1 signaling to drive NSCLC transformation and that PKCι phosphorylates ECT2 to promote ECT2-dependent lung adenocarcinoma, Justilien and colleagues further characterized the role of ECT2 in mutant Kras-Trp53 (KP) lung adenocarcinoma tumorigenesis. Ect2 depletion increased the survival of KP mice, decreased tumor burden and incidence, and decreased KP lung tumor-initiating cell (TIC) oncosphere formation and growth ex vivo. Further, Ect2 knockdown resulted in decreased soft-agar growth, which was rescued by wild-type ECT2 but not by a GEF-deficient ECT2 mutant (DHmut) or an ECT2 variant harboring a mutant nuclear localization signal (NLSmut). Similarly, ECT2 knockdown in lung tumor-initiating cells inhibited tumor growth in vivo, which was restored by the expression of wild-type ECT2, but not DHmut or NLSmut ECT2. Immunoprecipitation studies revealed that nuclear ECT2 bound to the ribosomal DNA (rDNA) transcription factor UBF1 and other ribosomal processing proteins, and regulated rDNA transcription, but not cytokinesis, in lung adenocarcinoma cells. Mechanistically, PKCι-mediated phosphorylation of ECT2 promoted the formation of the ECT2–UBF1 complex, which recruited RAC1 and the nucleolar protein nucleophosmin (NPM) to rDNA promoters to stimulate ECT2-regulated rDNA transcription. Treatment with an inhibitor of PKCι signaling prevented the phosphorylation of ECT2, inhibited the binding of ECT2, RAC1, and NPM to rDNA, and suppressed rRNA synthesis and KP transformed growth. These results elucidate the mechanism by which nuclear ECT2 drives mutant KRAS-TP53 lung adenocarcinoma initiation and transformed growth and identify a potential therapeutic strategy for targeting mutant KRAS–driven lung tumors.