Cooperation between Myc and YY1 provides novel silencing transcriptional targets of alpha 3 beta 1-integrin in tumour cells

We show that human osteosarcoma cells (Saos-2) have downregulation of alpha 3 beta 1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The alpha 3 gene was silenced in Saos-2 cells causing a low expression of alpha 3 beta 1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on alpha 3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the alpha 3 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 alpha 3-integrin promoter downregulation in normal osteoblasts. This downregulation of alpha 3 beta 1-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.