Cooperation between Myc and YY1 provides novel silencing transcriptional targets of α3β1-integrin in tumour cells

We show that human osteosarcoma cells (Saos-2) have downregulation of α3β1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The α3 gene was silenced in Saos-2 cells causing a low expression of α3β1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on α3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the α3 gene. This silencing mechanism involves the binding of Myc and YY1 to DNA and formation of complexes among Myc/Max, YY1, CREB-binding protein and deacetylation activity. The promoter containing deletions of E-boxes or YY1 cassettes failed to downregulate the transcription of a reporter gene as well as the inhibition of deacetylation activity. Overexpression of both Myc and YY1 was necessary to determine the α3-integrin promoter downregulation in normal osteoblasts. This downregulation of α3β1-integrin can contribute to the acquisition of a more aggressive phenotype. YY1 regulated negatively the Myc activity through a direct interaction with the Myc/Max and deacetylase complexes. This represents a novel silencing mechanism with broad implications in the transcription machinery of tumours.