Hypoxia-inducible factor 1 (HIF-1), recognized as a master transcription factor for adaptation to hypoxia, is associated with malignant characteristics and therapy resistance in cancers. It has become clear that cofactors such as ZBTB2 are critical for the full activation of HIF-1; however, the mechanisms downregulating the ZBTB2-HIF-1 axis remain poorly understood. In this study, we identified ZBTB7A as a negative regulator of ZBTB2 by analyzing protein sequences and structures. We found that ZBTB7A forms a heterodimer with ZBTB2, inhibits ZBTB2 homodimerization necessary for the full expression of ZBTB2-HIF-1 downstream genes, and ultimately delays the proliferation of cancer cells under hypoxic conditions. The Cancer Genome Atlas (TCGA) analyses revealed that overall survival is better in patients with high ZBTB7A expression in their tumor tissues. These findings highlight the potential of targeting the ZBTB7A-ZBTB2 interaction as a novel therapeutic strategy to inhibit HIF-1 activity and improve treatment outcomes in hypoxia-related cancers.
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ZBTB7A forms a heterodimer with ZBTB2 and inhibits ZBTB2 homodimerization required for full activation of HIF-1.
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Article Synopsis
- - ZBTB7A is one of three related transcription factors in humans (ZBTB7A, B, and C) that help control gene transcription involved in processes like blood cell formation, cancer development, and metabolism, particularly glycolysis.
- - These transcription factors have distinct DNA-binding domains and form specific connections with DNA sequences, particularly binding to motifs like G(a/c)CCC, which are crucial for their function.
- - In research focused on mutations in ZBTB7A linked to acute myeloid leukemia, it was found that most mutations hinder DNA binding, particularly those in the first two zinc-finger domains, which could also provide insights into the functions of ZBTB7B and ZBTB7C
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