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Computational Identification of a p38^SAPK-Regulated Transcription Factor Network Required for Tumor Cell Quiescence

¹ Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Mount Sinai School of Medicine, New York, New York and ² Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, SUNY-Albany, Rensselaer, New York

Requests for reprints: J.A. Aguirre-Ghiso, Division of Hematology and Oncology, Departments of Medicine and Otolaryngology, Mount Sinai School of Medicine, New York, NY, 10029. Phone: 212-241-4096; Fax: 212-241-4096, ext. 1079; E-mail: julio.aguirre-ghiso{at}mssm.edu.

Key Words: p38 • FoxM1 • BHLHB3 • c-Jun • p53 • quiescence

The stress-activated kinase p38 plays key roles in tumor suppression and induction of tumor cell dormancy. However, the mechanisms behind these functions remain poorly understood. Using computational tools, we identified a transcription factor (TF) network regulated by p38/β and required for human squamous carcinoma cell quiescence in vivo. We found that p38 transcriptionally regulates a core network of 46 genes that includes 16 TFs. Activation of p38 induced the expression of the TFs p53 and BHLHB3, while inhibiting c-Jun and FoxM1 expression. Furthermore, induction of p53 by p38 was dependent on c-Jun down-regulation. Accordingly, RNAi down-regulation of BHLHB3 or p53 interrupted tumor cell quiescence, while down-regulation of c-Jun or FoxM1 or overexpression of BHLHB3 in malignant cells mimicked the onset of quiescence. Our results identify components of the regulatory mechanisms driving p38-induced cancer cell quiescence. These may regulate dormancy of residual disease that usually precedes the onset of metastasis in many cancers. [Cancer Res 2009;69(14):5664–72]