Transcriptional Regulation of Yin-Yang 1 Expression through the Hypoxia Inducible Factor-1 in Pediatric Acute Lymphoblastic Leukemia

Yin-Yang transcription factor 1 (YY1) is involved in tumor progression, metastasis and has been shown to be elevated in different cancers, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood. Bioinformatics analysis reveal three Hypoxia-inducible factor 1-alpha (HIF-1 alpha) putative binding sites in the YY1 promoter region. The regulation of YY1 by HIF-1 alpha in leukemia was analyzed. Mutation of the putative YY1 binding sites in a reporter system containing the HIF-1 alpha promoter region and CHIP analysis confirmed that these sites are important for YY1 regulation. Leukemia cell lines showed that both proteins HIF-1 alpha and YY1 are co-expressed under hypoxia. In addition, the expression of mRNA of YY1 was increased after 3 h of hypoxia conditions and affect several target genes expression. In contrast, chemical inhibition of HIF-1 alpha induces downregulation of YY1 and sensitizes cells to chemotherapeutic drugs. The clinical implications of HIF-1 alpha in the regulation of YY1 were investigated by evaluation of expression of HIF-1 alpha and YY1 in 108 peripheral blood samples and by RT-PCR in 46 bone marrow samples of patients with pediatric acute lymphoblastic leukemia (ALL). We found that the expression of HIF-1 alpha positively correlates with YY1 expression in those patients. This is consistent with bioinformatic analyses of several databases. Our findings demonstrate for the first time that YY1 can be transcriptionally regulated by HIF-1 alpha, and a correlation between HIF-1 alpha expression and YY1 was found in ALL clinical samples. Hence, HIF-1 alpha and YY1 may be possible therapeutic target and/or biomarkers of ALL.