ZBTB10

ZBTB10 is a BTB-ZF transcription factor that uses tandem C2H2 zinc fingers to read specific DNA sequences and to regulate transcriptional programs across telomere biology, cancer metabolism, and immune cell activation (PMID:30629181, PMID:21156786). At telomeres, ZBTB10 binds the variant repeat TTGGGG with nanomolar affinity, co-localizes with a subset of telomeres in ALT-positive cells, and associates with the shelterin proteins TRF2/RAP1; a crystal structure of its ZF1-2 domain bound to TTGGGG defines the basis of sequence-specific recognition, where a single Arg767Gln substitution redirects preference toward the canonical TTAGGG repeat (PMID:30629181, PMID:36657642). As a transcriptional regulator it acts bidirectionally: it represses the Sp transcription factor family (Sp1/Sp3/Sp4) and their downstream targets including survivin, VEGF, and ErbB2 (PMID:21156786, PMID:22553354), directly represses PKLR to restrain glycolysis and neuroendocrine differentiation in prostate cancer (PMID:35306527), and directly binds and activates the HK1 and ARRDC3 promoters, the latter driving ITGB4 degradation and dampening PI3K/AKT signaling (PMID:37834257, PMID:39873948). ZBTB10 is also required for NF-κB activation in dendritic cells, where its loss derepresses NKRF and blocks p65/RelB nuclear translocation (PMID:33527393). Its expression is held in check post-transcriptionally by multiple miRNAs, including miR-27a, miR-361-5p, and miR-582-5p (PMID:21156786, PMID:35608340, PMID:42110628).

1. 2010 Medium

   Established ZBTB10 as a transcriptional repressor of the Sp family and placed it under miRNA control, defining its tumor-suppressive logic of Sp-dependent gene silencing.

   Evidence RNAi knockdown, overexpression, and miR-27a mimic/inhibitor with antioxidant rescue in colon cancer cells

   PMID:21156786

   Open questions at the time

   • Direct promoter binding of ZBTB10 at Sp gene loci not demonstrated
   • Mechanism of repression (corepressor recruitment) not defined
2. 2012 Medium

   Extended the miR-27a/ZBTB10/Sp axis to ErbB2-driven breast cancer and linked it to pharmacological induction, showing the axis is druggable.

   Evidence miR-27a mimic, ZBTB10 overexpression, CB1/CB2 antagonists and Sp RNAi in breast cancer lines

   PMID:22553354

   Open questions at the time

   • Direct vs indirect link between CB receptors and ZBTB10 unresolved
   • No biochemical demonstration of ZBTB10 binding ErbB2 regulatory regions
3. 2019 High

   Revealed an unexpected chromatin function by showing ZBTB10 binds the telomeric variant repeat TTGGGG directly and associates with shelterin at ALT telomeres, distinct from its Sp-repressor role.

   Evidence In vitro binding with affinity measurement, ALT-cell co-localization, and reciprocal Co-IP with TRF2/RAP1

   PMID:30629181

   Open questions at the time

   • Functional consequence of telomere binding for ALT maintenance not established
   • Whether telomeric and transcriptional roles are coupled is unknown
4. 2021 Medium

   Identified a positive regulatory role in innate immunity, showing ZBTB10 is required for NF-κB activation in dendritic cells via suppression of the repressor NKRF.

   Evidence shRNA knockdown in Mutu-DC, transcriptome analysis, p65/RelB translocation blots, and T cell co-culture

   PMID:33527393

   Open questions at the time

   • Whether ZBTB10 represses NKRF by direct promoter binding not shown
   • In vivo dendritic cell requirement not tested
5. 2022 Medium

   Defined ZBTB10 as a direct repressor of PKLR controlling glycolytic and neuroendocrine programs lost after androgen-deprivation therapy in prostate cancer.

   Evidence Loss/gain-of-function with reporter assays in prostate cancer cells

   PMID:35306527

   Open questions at the time

   • ChIP-level confirmation of ZBTB10 at the PKLR locus not reported
   • Mechanism linking AR signaling to ZBTB10 loss unclear
6. 2023 High

   Provided the atomic basis of variant-repeat recognition and a single-residue switch (Arg767Gln) that retargets ZBTB10 to canonical telomeric DNA.

   Evidence X-ray crystallography of wild-type and mutant ZF1-2/DNA complexes with ITC validation

   PMID:36657642

   Open questions at the time

   • Biological role of variant-repeat preference in cells not addressed
   • Structure does not resolve how full-length ZBTB10 engages shelterin
7. 2023 Medium

   Demonstrated ZBTB10 can act as a direct transcriptional activator by binding and activating the HK1 promoter, broadening its activity beyond repression.

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

   PMID:37834257

   Open questions at the time

   • Coactivators mediating activation not identified
   • Determinants of activator vs repressor mode unknown
8. 2025 Medium

   Connected ZBTB10 transcriptional activation of ARRDC3 to ITGB4 turnover and PI3K/AKT suppression, defining a tumor-suppressive output in gastric cancer.

   Evidence ChIP, Co-IP, reporter assays, xenografts, and phospho-proteomics

   PMID:39873948

   Open questions at the time

   • Direct ZBTB10 binding site within ARRDC3 promoter not finely mapped
   • Whether ARRDC3 is the sole effector unclear
9. 2025 Medium

   Showed exosomal miR-582-5p represses ZBTB10 to derepress TFR1 via H3K27ac, linking ZBTB10 loss to ferroptosis in renal tubular cells.

   Evidence 3′UTR dual-luciferase, miRNA overexpression, and H3K27ac ChIP

   PMID:42110628

   Open questions at the time

   • How ZBTB10 loss alters TFR1 promoter H3K27ac mechanistically not defined
   • Direct ZBTB10 occupancy at TFR1 not shown

• How ZBTB10's telomeric variant-repeat binding integrates with its dual transcriptional activator/repressor functions, and what dictates its mode and target selection in different tissues, remains unresolved.
• No unifying model linking telomere and promoter roles
• Cofactor partners distinguishing activation from repression unidentified
• In vivo physiological function not established