| 2006 |
The CLDN4 promoter contains two Sp1 binding sites both required for promoter activity; cells overexpressing CLDN4 exhibit low DNA methylation and high histone H3 acetylation of the critical Sp1-containing promoter region, whereas CLDN4-negative cells show the reverse; treatment with demethylating and/or acetylating agents induces CLDN4 expression in CLDN4-negative cells. |
Promoter deletion analysis, site-directed mutagenesis of Sp1 sites, ChIP for histone H3 acetylation, bisulfite sequencing for DNA methylation, pharmacological treatment with demethylating/acetylating agents |
The Journal of biological chemistry |
High |
16714763
|
| 2010 |
CLDN4 repression in normal ovarian epithelial cells is associated with bivalent histone modifications (H3K4me3 + H3K27me3) and DNA hypermethylation; during ovarian tumorigenesis, derepression correlates with loss of H3K27me3 and H4K20me3; combined DNA demethylation and histone acetylation treatment robustly reverses CLDN4 repression, whereas loss of H3K27me3 alone is insufficient. |
ChIP for H3K4me3, H3K27me3, H4K20me3; bisulfite sequencing; pharmacological treatment (demethylating + acetylating agents); gene expression analysis |
Carcinogenesis |
High |
20053926
|
| 2010 |
C-CPE (C-terminus of Clostridium perfringens enterotoxin) binds CLDN4 as a specific receptor, decreases CLDN4 protein expression, and relocates CLDN4 from cell-cell contact regions to the cytoplasm in ovarian cancer cells; C-CPE sensitizes EOC cells to Taxol and Carboplatin in a CLDN4-dependent manner and activates the ubiquitin-proteasome pathway. |
Quantitative RT-PCR, immunofluorescence, Western blot, 3D culture and monolayer culture assays, xenograft mouse model, oligonucleotide microarray |
Clinical cancer research |
Medium |
21123456
|
| 2007 |
STAT2 DNA-binding activity transcriptionally activates CLDN4 as an interferon-stimulated gene; siRNA knockdown of CLDN4 in fibroblasts reduces IFN-alpha/beta-induced antiproliferative and antiviral responses, consistent with cells expressing a DNA-binding mutant of STAT2. |
siRNA knockdown, gene microarray, site-directed mutagenesis of STAT2, biological IFN response assays (antiproliferative, antiviral) |
Journal of interferon & cytokine research |
Medium |
17651017
|
| 2019 |
PAK4 phosphorylates CEBPB on Thr-235, which then binds the -1093 to -991 bp region of the CLDN4 promoter to transcriptionally upregulate CLDN4 expression, promoting breast cancer cell migration and invasion; restoration of CLDN4 in PAK4-knockdown cells reverses inhibition of migration and invasion. |
PAK4 siRNA knockdown, CEBPB promoter ChIP/binding assay, luciferase reporter for CLDN4 promoter, rescue overexpression of CLDN4, migration/invasion assays |
Biochemical and biophysical research communications |
Medium |
30808546
|
| 2020 |
ZNF703 directly binds the CLDN4 promoter and transactivates CLDN4 expression to promote EMT and HCC metastasis; downregulation of CLDN4 attenuates ZNF703-mediated metastasis, and CLDN4 upregulation reverses the reduced metastasis seen upon ZNF703 knockdown. |
ChIP for ZNF703 binding to CLDN4 promoter, loss- and gain-of-function experiments, in vitro and in vivo metastasis assays, epistasis rescue |
Cell death & disease |
Medium |
32269215
|
| 2022 |
TGF-β signaling upregulates CLDN4 expression in GBM cells and promotes nuclear translocation of CLDN4; CLDN4 modulates the TNF-α/NF-κB signaling pathway; inhibition of CLDN4 suppresses mesenchymal transition, invasion, and migration, and TGF-β inhibitor ITD-1 downregulates CLDN4 and inhibits invasion. |
CLDN4 knockdown/overexpression, subcellular fractionation/imaging for nuclear translocation, TGF-β pathway inhibitor treatment, in vitro invasion/migration assays, in vivo tumor growth assays |
Cell death & disease |
Medium |
35418179
|
| 2023 |
RBM15, an m6A RNA methyltransferase, suppresses CLDN4 expression through m6A-mediated epigenetic inhibition in hepatic cells; RBM15 overexpression increases insulin resistance, and this effect is mediated through m6A regulation of CLDN4. |
MeRIP sequencing, mRNA-seq, RBM15 overexpression/knockdown, glucose uptake tests, Western blot, immunohistochemistry |
Molecular medicine |
Medium |
36803098
|
| 2023 |
IGF2BP3 interacts with CLDN4 mRNA and augments its stability in an m6A-dependent manner; CLDN4 upregulation by IGF2BP3 activates NF-κB signaling in gallbladder cancer cells; restoration of CLDN4 reverses the inhibitory effect of IGF2BP3 knockdown on gallbladder cancer progression. |
RNA immunoprecipitation (RIP), m6A methylation assays, IGF2BP3 knockdown/overexpression, NF-κB pathway analysis, rescue CLDN4 overexpression, in vitro/in vivo tumor assays |
Translational oncology |
Medium |
37643553
|
| 2023 |
FOXA1 transcriptionally activates CLDN4 by binding its promoter; CLDN4 overexpression induces activation of the PI3K/AKT pathway; celastrol inhibits GC progression by downregulating FOXA1, thereby reducing CLDN4 and impeding PI3K/AKT. |
Luciferase reporter assay for FOXA1 binding to CLDN4 promoter, FOXA1/CLDN4 overexpression/knockdown, Western blot for PI3K/AKT phosphorylation, MTT and Transwell assays |
Toxicology research |
Medium |
37397926
|
| 2022 |
CLDN4 knockdown in AML cells inhibits mRNA expression of PIK3R3 and MAP2K2, suppressing AKT and ERK1/2 activation; partial rescue of cell viability by AKT activator SC79 confirms AKT as a downstream effector; CLDN4 promotes AML cell growth and suppresses apoptosis. |
CLDN4 siRNA knockdown, Western blot for pAKT and pERK1/2, SC79 (AKT activator) rescue experiment, cell viability and apoptosis assays |
Biochemical and biophysical research communications |
Medium |
35760010
|
| 2022 |
In bladder urothelial carcinoma cells, demethylation-induced excess CLDN4 that is not integrated into tight junctions (TJ-unintegrated CLDN4 monomer) binds integrin β1, increases FAK phosphorylation, and promotes stemness, drug resistance, and metastatic ability; CLDN4 knockdown reduces FAK phosphorylation. |
Co-immunoprecipitation/pulldown of CLDN4 with integrin β1, Western blot for FAK phosphorylation, CLDN4 knockdown, demethylating agent (AZA) treatment, fractionation to identify TJ-unintegrated CLDN4 |
International journal of molecular sciences |
Medium |
35742959
|
| 2025 |
CLDN4 is palmitoylated at cysteine residues C104 and C107; this palmitoylation regulates ubiquitination at lysine K103, inhibits clathrin-mediated endocytosis, and sustains CLDN4 anchoring within lipid rafts; lipid raft-anchored CLDN4 drives mobilization of contactin-1 to lipid rafts and activates Notch signaling, promoting hepatic-to-biliary lineage transition and lenvatinib resistance in HCC. |
Palmitoylation site mutagenesis (C104/C107), ubiquitination assays, lipid raft fractionation, clathrin-mediated endocytosis assays, Co-IP for contactin-1, Notch pathway reporter assays, drug resistance assays |
Cell reports. Medicine |
High |
40592346
|
| 2025 |
CLDN4 knockout in SCLC cells promotes cell proliferation by accelerating cell cycle progression; CLDN4 knockout upregulates SAA1 which partly mediates the proliferation-promoting effect; CLDN4 expression is directly regulated by SP1, with DNA methylation also contributing to transcriptional regulation. |
CRISPR/CRISPR-based CLDN4 knockout, RNA-seq, SP1 binding assays, DNA methylation analysis, SAA1 knockdown rescue, cell cycle and proliferation assays |
Biochemical and biophysical research communications |
Medium |
41016339
|
| 2025 |
CLDN4 overexpression in corpus cavernosum smooth muscle cells activates the JNK signaling pathway, increases fibrotic protein expression, and impairs erectile function in vivo; hypoxia increases CLDN4 expression, and Cldn4 overexpression in rat corpus cavernosum increases local fibrosis and impairs erectile function. |
Lentiviral Cldn4 overexpression in vitro and in vivo (rat corpus cavernosum), Western blot for JNK pathway and fibrotic proteins, functional erectile assays, immunofluorescence |
The journal of sexual medicine |
Medium |
38477100
|
| 2025 |
CLDN4 knockdown in cerulein-stimulated pancreatic acinar cells reduces ROS, iron accumulation, inflammatory cytokines (TNF-α, IL-6, IL-17), restores GPX4 levels, and reduces ACSL4 expression, suppressing ferroptosis; CLDN4 knockdown decreases JAK2/STAT3 pathway activation, and combined CLDN4 knockdown with JAK2 inhibitor AG490 provides additive protective effects in AP models. |
shRNA CLDN4 knockdown, RNA-seq, Western blot for JAK2/STAT3, GPX4, ACSL4, ELISA for cytokines, flow cytometry for ROS, cerulein AP mouse model, pharmacological JAK2 inhibition (AG490) epistasis |
Functional & integrative genomics |
Medium |
40892111
|
| 2020 |
SPTBN2 interacts with CLDN4 to promote endometrial cancer cell migration and invasion via the PI3K/AKT pathway; CLDN4 overexpression partially reverses the decrease in migration/invasion caused by SPTBN2 knockdown, and CLDN4 is itself upregulated in EEC and promotes metastasis. |
Co-IP/interaction assay between SPTBN2 and CLDN4, SPTBN2/CLDN4 knockdown and overexpression, PI3K/AKT pathway western blot, migration/invasion assays, rescue epistasis |
Cell death discovery |
Low |
34887379
|
| 2025 |
AP-1 transcription factors (JUNB, FOSB, FOS) are required for CLDN4 induction in transitional AT2 cells following viral lung injury; CLDN4+ AT2 cells represent a KRT8-high transitional substate with chromatin enriched for AP-1 motifs; AP-1 promotes AT2 cell dispersion and senescence signaling toward fibroblasts. |
Mouse genetics (AP-1 member conditional knockout), multiomics (joint transcriptomic-epigenomic profiling), immunostaining, chromatin accessibility (ATAC-seq) for AP-1 motif enrichment, in vivo viral injury model |
bioRxivpreprint |
Medium |
|