ZBTB10

ZBTB10 is a BTB/POZ-zinc finger transcription factor that functions as a transcriptional repressor and activator, with additional roles in telomere biology and immune signaling. ZBTB10 represses Sp1, Sp3, and Sp4 transcription factors, thereby downregulating Sp-dependent target genes including cyclin D1, VEGF, survivin, and MDR1; its own expression is post-transcriptionally suppressed by miR-27a and miR-361-5p (PMID:21156786, PMID:35608340). Its two C2H2 zinc fingers bind variant telomeric TTGGGG repeats with nanomolar affinity—structurally resolved by crystallography—and its N-terminal region interacts with TRF2/RAP1, localizing ZBTB10 to ALT telomeres (PMID:30629181, PMID:36657642). ZBTB10 also directly binds and regulates the promoters of metabolic genes (HK1 activation, PKLR repression, ARRDC3 activation), modulating glycolysis and PI3K/AKT signaling in cancer contexts, and is required for NF-κB activation in conventional dendritic cells through repression of NKRF (PMID:37834257, PMID:35306527, PMID:39873948, PMID:33527393).

1. 2010 High

   Establishing ZBTB10 as the missing Sp transcription factor repressor resolved how ROS and miR-27a converge to control Sp-dependent oncogene programs.

   Evidence miR-27a modulation, ZBTB10 overexpression/RNAi, and antioxidant rescue in colon cancer cells

   PMID:21156786

   Open questions at the time

   • Whether ZBTB10 binds Sp gene promoters directly or acts indirectly was not established
   • No genome-wide target identification performed
   • Mechanism of ZBTB10-mediated Sp repression (competition vs. active repression) unclear
2. 2012 High

   Cross-cancer validation in breast and ovarian models confirmed the miR-27a/ZBTB10/Sp axis as a general oncogenic circuit rather than a colon cancer-specific phenomenon.

   Evidence ZBTB10 overexpression and miR-27a inhibition in breast and ovarian cancer lines; in vivo xenograft validation

   PMID:22407812 PMID:22553354 PMID:23254909

   Open questions at the time

   • Direct ZBTB10–DNA interaction at Sp promoters still not demonstrated
   • Physiological regulation of ZBTB10 beyond miRNA-mediated suppression unknown
3. 2019 High

   Discovery that ZBTB10 binds variant TTGGGG telomeric repeats and interacts with TRF2/RAP1 revealed an unexpected telomere biology function distinct from its Sp-repressor role.

   Evidence Quantitative DNA-binding assays, Co-IP, mass spectrometry, and fluorescence co-localization with telomeres in ALT-positive U2OS cells

   PMID:30629181

   Open questions at the time

   • Functional consequence of ZBTB10 loss at ALT telomeres not tested
   • Whether telomere binding and Sp repression are independent or coordinated is unknown
   • Role in telomere maintenance or recombination not addressed
4. 2021 Medium

   Showing that ZBTB10 is required for NF-κB activation in dendritic cells—by repressing NKRF—extended its functional repertoire to innate immune regulation.

   Evidence shRNA knockdown in Mutu-DC cDC1 line with transcriptome analysis, p65/RelB nuclear translocation assays, and T cell co-culture

   PMID:33527393

   Open questions at the time

   • Whether ZBTB10 directly binds the NKRF promoter was not tested
   • In vivo immune phenotype of ZBTB10 deficiency not established
   • Findings from a single immortalized DC line
5. 2022 Medium

   Identification of PKLR as a direct transcriptional target of ZBTB10 linked its loss to metabolic reprogramming and neuroendocrine differentiation in therapy-resistant prostate cancer.

   Evidence Loss-of-function studies and direct transcriptional regulation assays in prostate cancer cell lines

   PMID:35306527

   Open questions at the time

   • ChIP-based confirmation of direct promoter binding not explicitly shown
   • Mechanism coupling ZBTB10 loss to androgen-deprivation resistance not defined
6. 2023 High

   Solving the crystal structure of ZBTB10 ZF1-2 bound to TTGGGG DNA provided the atomic basis for variant repeat selectivity and showed a single residue switch (Arg767Gln) redirects binding to canonical TTAGGG.

   Evidence X-ray crystallography, ITC, and site-directed mutagenesis with co-crystal of mutant–TTAGGG complex

   PMID:36657642

   Open questions at the time

   • Full-length structural information including the BTB domain is lacking
   • Whether the Arg767Gln variant exists naturally is unknown
   • How zinc finger binding integrates with BTB domain-mediated protein interactions not resolved
7. 2023 Medium

   Demonstrating that ZBTB10 directly binds and activates the HK1 promoter established it as a context-dependent transcriptional activator, not solely a repressor.

   Evidence ChIP and luciferase reporter assays in laryngeal cancer and 293T cells with knockdown/overexpression

   PMID:37834257

   Open questions at the time

   • What determines whether ZBTB10 activates versus represses a given promoter is unknown
   • Co-factor requirements for activation not identified
8. 2025 High

   Identifying the ZBTB10→ARRDC3→ITGB4 ubiquitination axis that suppresses PI3K/AKT signaling defined a complete tumor-suppressive signaling chain from transcription factor to phospho-proteome.

   Evidence ChIP, Co-IP, luciferase reporter, RNA-seq, phosphoproteomics, and xenograft models in gastric cancer

   PMID:39873948

   Open questions at the time

   • Whether this axis operates in non-cancer tissues is untested
   • Upstream signals controlling ZBTB10 expression beyond miRNAs remain poorly characterized

• It remains unknown how ZBTB10's dual roles—Sp/promoter-level transcription regulation and variant telomeric repeat binding—are coordinated, what determines its activator versus repressor function at different promoters, and what its physiological role is in vivo.
• No in vivo knockout/conditional model phenotype reported
• Genome-wide binding profile (ChIP-seq) not published
• Functional consequence of telomeric binding on ALT mechanisms not tested