p73 is essential for vitamin D mediated osteoblastic differentiation

Abstract

The secosteroid hormone vitamin D3 (VD3) exerts its biological actions through its cognate receptor, the Vitamin D Receptor (VDR). Vitamin D3 and VDR play a key role in bone formation and keratinocyte differentiation, exert anti-proliferative actions in human cancer, and is widely used as a chemotherapeutic agent for cancer. Additionally, VD3 promotes differentiation of human osteosarcoma cells by up-regulating genes involved in cell cycle arrest and osteoblastic differentiation. Although considerable work has been carried out in understanding the molecular mechanisms underlying the VD3-mediated differentiation of human osteosarcoma cells, the upstream regulation of VD3 signaling pathway is still unclear. In this study we demonstrate that p73 acts as an upstream regulator of VD3 mediated osteoblastic differentiation. Transcription factor p73, a p53 homolog has been shown to play a role in development and recently been termed as a tumor suppressor. Silencing p73 results in a significant reduction of VD3 mediated osteoblastic differentiation; while DNA damage induced p73 leads to an increase in VD3 mediated differentiation of osteosarcoma cells. Together, our data implicate a novel role for p73 in vitamin D mediated differentiation of human osteosarcoma cells.