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

Abstract

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-1α) putative binding sites in the YY1 promoter region. The regulation of YY1 by HIF-1α in leukemia was analyzed. Mutation of the putative YY1 binding sites in a reporter system containing the HIF-1α promoter region and CHIP analysis confirmed that these sites are important for YY1 regulation. Leukemia cell lines showed that both proteins HIF-1α 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-1α induces downregulation of YY1 and sensitizes cells to chemotherapeutic drugs. The clinical implications of HIF-1α in the regulation of YY1 were investigated by evaluation of expression of HIF-1α 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-1α 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-1α, and a correlation between HIF-1α expression and YY1 was found in ALL clinical samples. Hence, HIF-1α and YY1 may be possible therapeutic target and/or biomarkers of ALL.

Hypoxia Mediated Glycoprotein-170 Expression: Role in Cancer Cells Chemo Resistance

“…These findings may show that hypoxia induces hypoxia expression of P-gp, which confers a mechanism of resistance to chemotherapy of some tumors [20]. On the other hand, the effects of hypoxia intensify the activity of other transcription factors that also participate in the regulation of the ABCB1 gene, as recently published by Antonio et al, where they show that HIF-1a transcriptionally regulates the factor of YY1 transcript, which in turn has been reported as a regulator of P-gp expression, this in a leukemic line, which could suggest that the effects of hypoxia would increase tumor susceptibility to drug resistance [21,22].…”

HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies

“…Conversely, inhibition of HIF-1α expression levels triggered the down-regulation of YY1, resulting in increased sensitivity of tumor cells to chemotherapeutic agents. 93 In peripheral blood (PB) and BM samples from ALL patients, the researchers also observed a positive regulation of YY1 expression with HIF-1α. 93 Overall, these results provide the first evidence that YY1 can be transcriptionally modulated by HIF-1α to exert an oncogenic effect.…”

“… DFO/ROS/HIF-1α 92 BM samples of ALL patients/leukemia cell lines Oncogene Chemical inhibition of HIF-1α induced down-regulation of YY1, sensitizing cells to chemotherapeutic agents. HIF-1α/YY1 93 Human T-ALL cell samples/mice Oncogene HIF-1α KD restored the activity of mTOR at low oxygen concentrations, thereby regaining chemosensitivity in T-ALL cells. HIF-1α/mTOR 94 CLL lines/mice Oncogene SC could induce up-regulation of HIF-1α in CLL cells, ultimately promoting the survival of CLL cells.…”

Transcriptional Regulation and Its Misregulation in Human Diseases

“…In this Special Issue, a total of 18 excellent and interesting papers [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], consisting of 13 original research studies [3][4][5][6][10][11][12][14][15][16][18][19][20], as well as five reviews, are published [7][8][9]13,17]. They cover many subjects of transcriptional regulation, including studies on cis-regulatory elements, transcription factors (TF), chromatin regulators, and ncRNAs.…”

“…Another TF, which is involved in tumor progression and metastasis is Yin-Yang transcription factor 1 (YY1); indeed, it also overexpressed in different cancers, including leukemia. Antonio-Andres, G et al [5] observed that the expression of YY1 in patients with pediatric acute lymphoblastic leukemia (ALL) positively correlates with HIF1A transcription. Besides, their findings clearly indicate, for the first time, that YY1 is transcriptionally regulated by HIF-1α and suggest that both HIF1A and YY1 transcription factors could be possible therapeutic targets and/or biomarkers of ALL [5].…”