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

Abstract

Increased expression of A 6 B 4 integrin in several epithelial cancers promotes tumor progression; however, the mechanism underlying its transcriptional regulation remains unclear. Here, we show that depletion of homeodomaininteracting protein kinase 2 (HIPK2) activates B 4 transcription that results in a strong increase of B 4 -dependent mitogenactivated protein kinase and Akt phosphorylation, anchorageindependent growth, and invasion. In contrast, stabilization of HIPK2 represses B 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 B 4 transcription. Consistent with our in vitro findings, a strong correlation between B 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 B 4 transcription. These data, by revealing that B 4 expression is transcriptionally repressed in tumors by HIPK2 and p53 to impair B 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 B 4 transcription.

miR-221/222 control luminal breast cancer tumor progression by regulating different targets

“…46 The increase in β4 expression in cancers of epithelial origin has suggested that β4 expression might be regulated, at least in part, at the transcriptional level. 47 In the present study, we demonstrate, for the first time, that β4 integrin expression is under the control of miR-221/222 in the MCF-7 cell line, a known breast carcinoma cell line of the luminal subtype. 48 The concept of miR-221/222 dictating tumor aggressiveness by regulating β4 expression was then further validated by functional studies.…”

HIPK2 downregulates vimentin and inhibits breast cancer cell invasion

“…3B); however, it was previously shown that HIPK2 depletion increases colon cancer cell invasion by de-repressing the pro-invasive integrin b4. 42 Although ADR is currently considered one of the most effective agents in the treatment of breast cancers, drug resistance represents a major obstacle to successful outcome in many patients. 27 This perspective strongly suggests to identify novel therapeutical strategies to overcome drug resistance and inhibit tumor progression.…”

Counteracting MDM2‐induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells

“…Indeed we previously showed a correlation between low HIPK2 expression and bad outcome in wild-type p53 expressing colon cancer tumors [14]. HIPK2 cytoplasmic localization may also affect p53 apoptotic function, following overexpression of oncogenes such as CBFb-SMMHC in a leukemogenesis model [22,23], high-mobility group A1 (HMGA1) [24] or b4 integrin in breast cancers [25]. HIPK2 can be downregulated by several E3 ubiquitin ligases such as WD40-repeat/SOCS box protein WSB-1, the RING family ligases Siah-1 and Siah-2 and, MDM2 oncogene [21].…”