Human Homeobox HOXA7 Regulates Keratinocyte Transglutaminase Type 1 and Inhibits Differentiation

Abstract

Keratinocyte proliferation and differentiation result from expression of specific groups of genes regulated by unique combinations of transcription factors. To better understand these regulatory processes, we studied HOXA7 expression and its regulation of differentiation-specific keratinocyte genes. We isolated the homeobox transcription factor HOXA7 from keratinocytes through binding to a differentiation-dependent viral enhancer and analyzed its effect on endogenous differentiation-dependent genes, primarily transglutaminase 1. HOXA7 overexpression repressed transglutaminase 1-reporter activity. HOXA7 message markedly decreased, and transglutaminase RNA increased, upon phorbol ester-induced differentiation, in a protein kinase C-dependent manner. Overexpression of HOXA7 attenuated the transglutaminase 1 induction by phorbol ester, demonstrating that HOXA7 expression is inversely related to keratinocyte differentiation, and to transglutaminase 1 expression. Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. In keeping with these observations, epidermal growth factor receptor activation stimulated HOXA7 expression. HOX genes function in groups, and we found that HOXA5 and HOXB7 were also down-regulated by phorbol ester. These results provide the first example of protein kinase C-mediated homeobox gene regulation in keratinocytes, and new evidence that HOXA7, potentially in conjunction with HOXA5 and HOXAB7, silences differentiation-specific genes during keratinocyte proliferation, that are then released from inhibition in response to differentiation signals.