{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZBTB2 is a transcription factor of the POK family that plays a crucial role in cell cycle regulation. It acts as a potent repressor of the ARF‐HDM2‐p53‐p21 pathway by binding directly to key promoter elements and interfering with transcriptional activators such as p53 and Sp1. This results in the downregulation of cell cycle arrest molecules and promotes cell proliferation, indicating a proto‐oncogenic function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its impact on cell cycle regulation, ZBTB2 contributes to tumorigenesis through metabolic reprogramming. In bladder cancer cells, for instance, upregulation of ZBTB2—mediated by noncoding RNA networks that sequester miR‐4316—leads to repression of p21 and facilitation of PDK4 transcription, thereby shifting glucose metabolism toward glycolysis to favor rapid tumor cell growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the epigenetic level, ZBTB2 selectively binds methylated DNA sequences; however, this interaction is impaired when 5-methylcytosine is oxidized to 5-hydroxymethylcytosine. This finding underscores a role for ZBTB2 in modulating gene expression via DNA methylation dynamics, particularly at regulatory elements controlling genes like p21 that are central to cell cycle control."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nZBTB2 may also influence the tumor microenvironment. In uremic conditions, lower expression of ZBTB2 is associated with increased M2 macrophage infiltration, suggesting that aberrant regulation of ZBTB2 levels might contribute to inflammatory responses and fibrotic processes within diseased tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, ZBTB2 functions as an important cofactor in hypoxia signaling. By forming homodimers, it enhances the transactivation of hypoxia-inducible factor 1 (HIF-1) target genes through its recruitment to hypoxia-responsive elements and promotion of p300-mediated histone acetylation. This activity, which is negatively modulated by ZBTB7A, ultimately contributes to enhanced cancer cell invasion, metastasis, and proliferation under hypoxic conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nProteomic studies have further revealed that ZBTB2 engages in extensive protein–protein interactions with chromatin remodeling complexes, including the NuRD complex and components of the WICH and SWI/SNF assemblies. These interactions emphasize its multifaceted role in regulating chromatin structure and gene expression on a genome-wide scale."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, in the setting of oral squamous cell carcinoma, downregulation of ZBTB2—achieved through a miRNA-mediated pathway involving LIN28B—correlates with suppressed tumor progression. This highlights the potential of targeting the ZBTB2 regulatory axis as a therapeutic strategy in cancer treatment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bu-Nam Jeon, Won-Il Choi, Mi-Young Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZBTB2, a novel master regulator of the p53 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M809559200"}], "href": "https://doi.org/10.1074/jbc.M809559200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19380588"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19380588"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Min-Young Kim, Dong-In Koh, Won-Il Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkv026"}], "href": "https://doi.org/10.1093/nar/gkv026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25609694"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25609694"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Céline Lafaye, Ewa Barbier, Audrey Miscioscia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA binding of the p21 repressor ZBTB2 is inhibited by cytosine hydroxymethylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2014.02.122"}], "href": "https://doi.org/10.1016/j.bbrc.2014.02.122"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24607898"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24607898"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jianling Song, Ben Ke, Xiangdong Fang "}, {"type": "b", "children": [{"type": "t", "text": "APC and ZBTB2 May Mediate M2 Macrophage Infiltration to Promote the Development of Renal Fibrosis: A Bioinformatics Analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2024/5674711"}], "href": "https://doi.org/10.1155/2024/5674711"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39328595"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39328595"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Gouki Kambe, Minoru Kobayashi, Hiroshi Ishikita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZBTB7A forms a heterodimer with ZBTB2 and inhibits ZBTB2 homodimerization required for full activation of HIF-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2024.150604"}], "href": "https://doi.org/10.1016/j.bbrc.2024.150604"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39197198"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39197198"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Christalle C T Chow, Minoru Kobayashi, Gouki Kambe, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "ZBTB2 protein is a new partner of the Nucleosome Remodeling and Deacetylase (NuRD) complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biol Macromol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ijbiomac.2020.12.029"}], "href": "https://doi.org/10.1016/j.ijbiomac.2020.12.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33301849"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33301849"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Chuang Qi, Lu Zhang, Wenping Wang "}, {"type": "b", "children": [{"type": "t", "text": "The novel circ_0004674/miR-139-5p/ZBTB2 regulatory cascade inhibits the development of oral squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Head Neck (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hed.27779"}], "href": "https://doi.org/10.1002/hed.27779"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38665011"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38665011"}]}]}]}