Computational Identification of a p38SAPK -Regulated Transcription Factor Network Required for Tumor Cell Quiescence

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 14; pp. 5664 - 5672
• Main Authors: ADAM, Alejandro P, GEORGE, Ajish, SCHEWE, Denis, BRAGADO, Paloma, IGLESIAS, Bibiana V, RANGANATHAN, Aparna C, KOURTIDIS, Antonis, CONKLIN, Douglas S, AGUIRRE-GHISO, Julio A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-07-2009
• Subjects: Animals; Antineoplastic agents; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Cell Line, Tumor; Chick Embryo; Computational Biology - methods; Forkhead Box Protein M1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Profiling; Humans; Imidazoles - pharmacology; Immunoblotting; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Pyridines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Signal transduction; Identification; Transcription factor; Tumor cell; Network; Quiescence
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3820

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 p38alpha/beta 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.