Zbtb2, zinc finger and BTB domain-containing protein 2, is a protein belonging to the BTB/POZ zinc-finger family. It plays diverse roles in multiple biological processes. It is involved in the p53 and hypoxia-inducible factor 1 (HIF-1) pathways, and is associated with cell proliferation, cancer development, and gene expression regulation [1,4,5,8]. Gene knockout models would be valuable to further explore its functions.

In cancer, p53 deficiency triggers HIF-1-dependent hypoxia signaling through Zbtb2. Zbtb2 forms homodimers to increase HIF-1 transactivation activity only when p53 is non-functional, promoting invasion, metastasis, and growth of p53-deficient cancers. High intratumoral Zbtb2 levels are linked to poor prognosis in lung cancer patients, and Zbtb2 N-terminus-mimetic polypeptides can suppress the Zbtb2-HIF-1 axis, leading to antitumor effects [1]. Also, Zbtb2 is recruited to a subset of HIF-1 target loci to enhance their gene expression under hypoxia [2]. In addition, Zbtb2 was found to repress HIV-1 transcription, and its function is regulated by HIV-1 Vpr and cellular DNA damage responses [3]. It is also a new partner of the Nucleosome Remodeling and Deacetylase (NuRD) complex [4], reads unmethylated CpG island promoters and regulates embryonic stem cell differentiation [5], increases PDK4 expression by transcriptional repression of RelA/p65 [6], and may be involved in CXCL12/CXCR7-induced metastasis of colorectal cancer through crosstalk with cancer-associated fibroblasts [7]. In the p53 pathway, Zbtb2 represses transcription of ARF, p53, and p21 genes, while activating the HDM2 gene, acting as a potential proto-oncogenic master control gene of the p53 pathway [8]. Bioinformatics analysis suggests that Zbtb2 may mediate M2 macrophage infiltration to promote renal fibrosis [9]. Moreover, ZBTB7A forms a heterodimer with Zbtb2, inhibits Zbtb2 homodimerization, and delays cancer cell proliferation under hypoxic conditions [10].

In summary, Zbtb2 has crucial functions in multiple biological processes and disease conditions, especially in cancer and virus-host interactions. Studies using gene knockout models, if available, could provide more insights into its precise roles in these specific disease areas, furthering our understanding of its functions and potentially leading to new therapeutic strategies.

References:

1. Koyasu, Sho, Horita, Shoichiro, Saito, Keisuke, Hammond, Ester M, Harada, Hiroshi. 2022. ZBTB2 links p53 deficiency to HIF-1-mediated hypoxia signaling to promote cancer aggressiveness. In EMBO reports, 24, e54042. doi:10.15252/embr.202154042. https://pubmed.ncbi.nlm.nih.gov/36341521/

2. Chow, Christalle C T, Kobayashi, Minoru, Kambe, Gouki, Harada, Hiroshi. 2023. ZBTB2 is Recruited to a Specific Subset of HIF-1 Target Loci to Facilitate Full Gene Expression Under Hypoxia. In Journal of molecular biology, 435, 168162. doi:10.1016/j.jmb.2023.168162. https://pubmed.ncbi.nlm.nih.gov/37257772/

3. Bruce, James W, Bracken, Megan, Evans, Edward, Sherer, Nathan, Ahlquist, Paul. 2021. ZBTB2 represses HIV-1 transcription and is regulated by HIV-1 Vpr and cellular DNA damage responses. In PLoS pathogens, 17, e1009364. doi:10.1371/journal.ppat.1009364. https://pubmed.ncbi.nlm.nih.gov/33635925/

4. Russo, Rosita, Russo, Veronica, Cecere, Francesco, Chambery, Angela, Baglivo, Ilaria. 2020. ZBTB2 protein is a new partner of the Nucleosome Remodeling and Deacetylase (NuRD) complex. In International journal of biological macromolecules, 168, 67-76. doi:10.1016/j.ijbiomac.2020.12.029. https://pubmed.ncbi.nlm.nih.gov/33301849/

5. Karemaker, Ino D, Vermeulen, Michiel. 2018. ZBTB2 reads unmethylated CpG island promoters and regulates embryonic stem cell differentiation. In EMBO reports, 19, . doi:10.15252/embr.201744993. https://pubmed.ncbi.nlm.nih.gov/29437775/

6. Kim, Min-Young, Koh, Dong-In, Choi, Won-Il, Kim, Se-Hoon, Hur, Man-Wook. 2015. ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65. In Nucleic acids research, 43, 1609-25. doi:10.1093/nar/gkv026. https://pubmed.ncbi.nlm.nih.gov/25609694/

7. Wang, Dong, Wang, Xiaohui, Song, Yujia, Qu, Xianjun, Yu, Xinfeng. 2022. Exosomal miR-146a-5p and miR-155-5p promote CXCL12/CXCR7-induced metastasis of colorectal cancer by crosstalk with cancer-associated fibroblasts. In Cell death & disease, 13, 380. doi:10.1038/s41419-022-04825-6. https://pubmed.ncbi.nlm.nih.gov/35443745/

8. Jeon, Bu-Nam, Choi, Won-Il, Yu, Mi-Young, Yun, Chae-Ok, Hur, Man-Wook. 2009. ZBTB2, a novel master regulator of the p53 pathway. In The Journal of biological chemistry, 284, 17935-46. doi:10.1074/jbc.M809559200. https://pubmed.ncbi.nlm.nih.gov/19380588/

9. Song, Jianling, Ke, Ben, Fang, Xiangdong. 2024. APC and ZBTB2 May Mediate M2 Macrophage Infiltration to Promote the Development of Renal Fibrosis: A Bioinformatics Analysis. In BioMed research international, 2024, 5674711. doi:10.1155/2024/5674711. https://pubmed.ncbi.nlm.nih.gov/39328595/

10. Kambe, Gouki, Kobayashi, Minoru, Ishikita, Hiroshi, Hammond, Ester M, Harada, Hiroshi. 2024. ZBTB7A forms a heterodimer with ZBTB2 and inhibits ZBTB2 homodimerization required for full activation of HIF-1. In Biochemical and biophysical research communications, 733, 150604. doi:10.1016/j.bbrc.2024.150604. https://pubmed.ncbi.nlm.nih.gov/39197198/