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

Abstract Increased expression of α6β4 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]

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