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Negative Regulation of β₄ Integrin Transcription by Homeodomain-Interacting Protein Kinase 2 and p53 Impairs Tumor Progression

¹ Molecular Oncogenesis Laboratory, Department of Experimental Oncology, and ² Department of Pathology, Regina Elena Cancer Institute, Rome, Italy; ³ Department of Oncology and Neurosciences, University of Chieti, Chieti, Italy; and ⁴ Department of Internal Medicine, University of Turin, Turin, Italy

Requests for reprints: Rita Falcioni, Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, Via delle Messi d'Oro, 156, 00158 Rome, Italy. Phone: 39-6-52662535; Fax: 39-6-52662505; E-mail: falcioni{at}ifo.it.

Key Words: integrin ₆β₄ • HIPK2 • p53 family members • transcription • tumor progression

Increased expression of ₆β₄ integrin in several epithelial cancers promotes tumor progression; however, the mechanism underlying its transcriptional regulation remains unclear. Here, we show that depletion of homeodomain-interacting protein kinase 2 (HIPK2) activates β₄ transcription that results in a strong increase of β₄-dependent mitogen-activated protein kinase and Akt phosphorylation, anchorage-independent growth, and invasion. In contrast, stabilization of HIPK2 represses β₄ expression in wild-type p53 (wtp53)-expressing cells but not in p53-null cells or cells expressing mutant p53, indicating that HIPK2 requires a wtp53 to inhibit β₄ transcription. Consistent with our in vitro findings, a strong correlation between β₄ overexpression and HIPK2 inactivation by cytoplasmic relocalization was observed in wtp53-expressing human breast carcinomas. Under loss of function of HIPK2 or p53, the p53 family members TAp63 and TAp73 strongly activate β₄ transcription. These data, by revealing that β₄ expression is transcriptionally repressed in tumors by HIPK2 and p53 to impair β₄-dependent tumor progression, suggest that loss of p53 function favors the formation of coactivator complex with the TA members of the p53 family to allow β₄ transcription. [Cancer Res 2009;69(14):5978–86]