Negative Regulation of ₄ Integrin Transcription by Homeodomain-Interacting Protein Kinase 2 and p53 Impairs Tumor Progression

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

^* To whom correspondence should be addressed. E-mail: falcioni{at}ifo.it.

	Abstract

Increased expression of ₆₄ 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 ₄ transcription that results in a strong increase of ₄-dependent mitogen-activated protein kinase and Akt phosphorylation, anchorage-independent growth, and invasion. In contrast, stabilization of HIPK2 represses ₄ 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 ₄ transcription. Consistent with our in vitro findings, a strong correlation between ₄ 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 ₄ transcription. These data, by revealing that ₄ expression is transcriptionally repressed in tumors by HIPK2 and p53 to impair ₄-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 ₄ transcription. [Cancer Res 2009;69(14):5978–86]

Key Words: integrin ₆₄, HIPK2, p53 family members, transcription, tumor progression