Biglycan · UniProt P21810
BGN (biglycan) is an X-linked extracellular matrix small leucine-rich proteoglycan that functions both as a structural matrix component and as a signaling ligand engaging innate-immune and developmental pathways (PMID:1968422, PMID:36632455). As a secreted ligand, BGN binds TLR2/TLR4 to activate NF-κB signaling: in colon cancer it drives NF-κB-dependent H3K27me3 silencing of SLC26A2 and ST6GalNAc6 to suppress immunosuppressive Siglec-7 ligand synthesis (PMID:32050430), in gastric cancer it transforms mesothelial cells into cancer-associated fibroblast-like cells through a STAT3-reinforced positive feedback loop (PMID:36632455), and CAF-derived BGN signals through TLR4 to activate Erk and NF-κB and promote tumor cell proliferation, migration, and M2 macrophage polarization (PMID:41465449). BGN also activates canonical Wnt/β-catenin signaling, a role required for CLIC5-dependent myogenic differentiation and satellite cell function in skeletal muscle (PMID:39999205) and exploited in gastric cancer EMT downstream of GLIS2-driven transcription (PMID:40936440). Through its leucine-rich repeat domain BGN engages TGF-β and promotes BMP/Smad-dependent osteogenesis, with bone-forming activity controlled by miR-185 and miR-330-5p (PMID:27236923, PMID:30787286, PMID:32374006), and it directly binds the NOTCH3 ectodomain, accumulating in CADASIL arteries (PMID:25578324). BGN abundance is set by FBXW7-mediated ubiquitination of the protein and by PDK1-enhanced mRNA stability that couples to NF-κB activation (PMID:35273678, PMID:39578715). Loss-of-function and missense BGN mutations cause X-linked spondyloepimetaphyseal dysplasia, with structural modeling implicating disrupted TGF-β binding (PMID:27236923).
Establishing the chromosomal location and structure of BGN was the first step toward connecting the gene to X-linked phenotypes.
Evidence Southern analysis of human-rodent somatic cell hybrid DNAs
Fine-mapping refined BGN's position within Xq28 and nominated it as a candidate for an X-linked chondrodysplasia, framing it as a skeletal-disease gene.
Evidence Breakpoint-defined somatic hybrid cell line panel
Determining that BGN is subject to X inactivation yet shows pseudo-autosomal expression resolved how its dosage is regulated across sex chromosome complements.
Evidence Hybrid cell line X-inactivation analysis with patient mRNA/protein profiling
Demonstrating a direct BGN-NOTCH3 ectodomain interaction placed BGN within cerebrovascular smooth muscle signaling and CADASIL pathology.
Evidence Direct protein interaction assay, co-incubation with purified NOTCH3 ectodomain, rapamycin treatment
Identifying causative BGN missense mutations established BGN as the gene for X-linked spondyloepimetaphyseal dysplasia and proposed disrupted TGF-β binding as the mechanism.
Evidence Exome sequencing across three families plus 3D structural simulation of BGN-TGF-β interaction
Mapping the BGN-TLR4-NF-κB axis to epigenetic silencing of glycosyltransferase genes connected BGN to tumor immune evasion via Siglec-7 ligand suppression.
Evidence shRNA knockdown, ChIP for H3K27me3, NF-κB reporter, glycan binding/flow cytometry in colon cancer cells
Placing BGN downstream of osteogenic miRNAs (miR-185, miR-330-5p) defined how BGN expression is tuned to control BMP/Smad-dependent bone formation.
Evidence Dual-luciferase reporter assays, miR knockout/inhibitor experiments, OVX mouse models with micro-CT
Identifying FBXW7-mediated ubiquitination of BGN revealed post-translational control of BGN protein stability through the ubiquitin-proteasome system.
Evidence Co-IP, ChIRP, RIP, RNA pull-down, luciferase reporter linking lncRNA SEMA3B-AS1/HMGB1 to FBXW7
Showing BGN binds TLR2/TLR4 to reprogram mesothelial cells into CAF-like cells, reinforced by a STAT3 feedback loop, established a self-amplifying BGN circuit in the gastric tumor stroma.
Evidence Co-IP, nuclear/cytoplasmic fractionation, rescue experiments
Linking CLIC5 to BGN-driven Wnt/β-catenin activation defined a physiological role for BGN in myogenic differentiation and muscle regeneration.
Evidence Muscle-specific CLIC5 knockout mice, myoblast differentiation assays, protein interaction studies, Wnt reporter
Demonstrating PDK1 stabilizes BGN mRNA and physically interacts with BGN to activate NF-κB added a cytoplasmic, mRNA-stability mode of BGN regulation in ovarian cancer.
Evidence Co-IP, co-localization imaging, RNA stability assay, RNA-seq, rescue experiments
Multiple transcriptional regulators (GLIS2, REST via HCN2) and recombinant-BGN/TLR4 experiments extended the BGN-Wnt and BGN-NF-κB/Erk axes across esophageal, gastric, and bladder cancers and to ferroptosis suppression.
Evidence Recombinant BGN + TLR4 blockade, ChIP, dual-luciferase reporters, knockdown/rescue and in vivo assays
PMID:40936440 PMID:41465449 PMID:42074076
Functional assays of a Meester-Loeys syndrome BGN variant tied the mutation to reduced canonical Wnt and TGF-β reporter activity, though patient fibroblasts showed no consistent signaling change.
Evidence Luciferase reporter assays in mutant-BGN-expressing cell lines, nuclear fractionation of patient fibroblasts
Spatial and single-cell analyses positioned CAF-derived BGN within a BGN/MDK axis shaping the melanoma microenvironment and proposed m6A control of BGN.
Evidence Spatial transcriptomics, scRNA-seq, CellChat, m6A regulator assays, in vitro/in vivo functional assays
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 1990 | BGN (biglycan) gene was localized to human chromosome Xq13-qter by Southern analysis of human-rodent somatic cell hybrid DNAs; the gene is approximately 6 kb in length and present as a single copy. | Southern blot analysis of somatic cell hybrid DNAs | Genomics | High | 1968422 |
| 1992 | BGN was fine-mapped within Xq28, proximal to red/green cone pigment genes and G6PD, and distal to DXS304/DXS305/GABRA3, identifying it as a candidate gene for X-linked dominant chondrodysplasia punctata. | Somatic hybrid cell line panel with defined X chromosome breakpoints | Genomics | Medium | 1612609 |
| 1995 | BGN is subject to X inactivation (demonstrated via hybrid cell lines) but displays pseudo-autosomal expression behavior, likely regulated by a trans-acting gene that escapes X inactivation rather than by escape of BGN itself or a Y-chromosomal homolog. | Hybrid cell line analysis, mRNA and protein expression profiling in patients with varying sex chromosome numbers | Human genetics | Medium | 7607653 |
| 2015 | BGN protein directly interacts with NOTCH3 ectodomain protein in cell culture and in direct protein interaction assays; BGN accumulates in CADASIL arteries and cerebrovascular smooth muscle cells upregulate BGN in response to NOTCH3 ectodomain via an mTOR-sensitive mechanism. | Direct protein interaction assay, cell culture co-incubation with purified NOTCH3 ectodomain, rapamycin (mTOR inhibitor) treatment, immunoblotting, in situ hybridization | Translational stroke research | Medium | 25578324 |
| 2016 | Missense mutations in BGN (p.Lys147Glu and p.Gly259Val) cause X-linked recessive spondyloepimetaphyseal dysplasia; 3D structural simulation placed both mutated residues in the concave arc of leucine-rich repeat domains that interact with TGF-β, implicating disrupted TGF-β binding as the pathogenic mechanism. | Exome sequencing, 3D structural simulation of BGN–TGF-β interaction | American journal of human genetics | Medium | 27236923 |
| 2019 | BGN is a direct transcriptional target of miR-185; depletion of miR-185 increases BGN expression and promotes osteogenesis through the BMP/Smad pathway, as identified by dual-luciferase reporter assay and validated in miR-185 knockout mouse osteoblasts and an OVX osteoporosis model. | Dual-luciferase reporter assay, miR-185 knockout mouse model, micro-CT bone analysis | Cell death & disease | Medium | 30787286 |
| 2020 | BGN acts via TLR4 to activate NF-κB, which epigenetically silences (via H3K27me3) the promoters of SLC26A2 and ST6GalNAc6, suppressing synthesis of immunosuppressive Siglec-7 ligands in colon cancer cells; BGN and TLR4 form a positive feedback loop. | shRNA knockdown of BGN and TLR4, ChIP for H3K27me3, NF-κB reporter assay, glycan binding/flow cytometry | Cells | Medium | 32050430 |
| 2020 | BGN silencing by miR-330-5p (validated by dual-luciferase reporter and Western blot) suppresses BMP/Smad pathway activity, ALP activity, and mineralization in bone marrow stromal cells; BGN overexpression reverses these effects, placing BGN downstream of miR-330-5p in osteogenic signaling. | Dual-luciferase reporter assay, Western blot, miR-330-5p inhibitor transfection, OVX mouse model with micro-CT | European review for medical and pharmacological sciences | Medium | 32374006 |
| 2020 | In glioblastoma, PHF20 interacts with WDR5 and activates WISP1 transcription; WISP1 and BGN then act together to regulate β-catenin degradation, sustaining GBM stem cell-like phenotype. | Co-immunoprecipitation, promoter binding assays, PHF20 knockout cell lines | Frontiers in oncology | Low | 33117706 |
| 2022 | FBXW7 E3 ubiquitin ligase mediates ubiquitination of BGN protein; lncRNA SEMA3B-AS1 binds HMGB1 to transcriptionally regulate FBXW7, thereby controlling BGN protein stability via the ubiquitin-proteasome system. | Co-immunoprecipitation, ChIRP, RNA immunoprecipitation, RNA pull-down, luciferase reporter assay | Oxidative medicine and cellular longevity | Medium | 35273678 |
| 2023 | BGN binds TLR2/TLR4 on mesothelial cells to activate NF-κB signaling, driving their transformation into cancer-associated fibroblast-like cells; activated STAT3 in gastric cancer cells then promotes BGN transcription, creating a BGN/FAP-STAT3 positive feedback loop. | Co-immunoprecipitation, nuclear/cytoplasmic protein extraction, recovery (rescue) experiments | International journal of biological sciences | Medium | 36632455 |
| 2024 | CLIC5 promotes myogenic differentiation and skeletal muscle regeneration via direct interaction with BGN, which activates the canonical Wnt/β-catenin signaling pathway; CLIC5 deletion impairs BGN-mediated Wnt/β-catenin activity and reduces satellite cell differentiation potential. | CLIC5 muscle-specific knockout mice, in vitro myoblast differentiation assays, protein interaction studies, Wnt/β-catenin pathway reporter | Science advances | Medium | 39999205 |
| 2024 | PDK1 co-localizes and physically interacts with BGN in the cytoplasm of ovarian cancer cells; PDK1 positively regulates BGN expression by enhancing BGN mRNA stability, and this PDK1–BGN interaction activates the NF-κB oncogenic pathway. | Co-immunoprecipitation, co-localization imaging, RNA stability assay, RNA sequencing, BGN overexpression rescue experiments | Acta biochimica et biophysica Sinica | Medium | 39578715 |
| 2025 | CAF-derived BGN signals through TLR4 on esophageal squamous cell carcinoma cells to activate Erk and NF-κB signaling pathways, promoting cancer cell proliferation and migration; TLR4 blockade abolishes these effects. BGN also promotes M2-like macrophage polarization. | Recombinant human BGN treatment, TLR4 blocking antibody, co-culture model, cDNA microarray, Western blot | International journal of molecular sciences | Medium | 41465449 |
| 2025 | GLIS2 transcription factor directly binds the BGN promoter to enhance BGN transcription, thereby activating Wnt/β-catenin signaling and promoting EMT in gastric cancer; Wnt/β-catenin inhibitor XAV-939 blocks BGN-driven tumor-promoting effects. | GLIS2 knockdown/BGN overexpression rescue experiments, Wnt pathway inhibitor XAV-939, analysis of 18 paired GC tissue samples | The Kaohsiung journal of medical sciences | Low | 40936440 |
| 2025 | Mutant BGN (Meester-Loeys syndrome missense variant) reduces canonical Wnt and TGF-β signaling activity as measured by reporter vector assays in cell lines expressing mutant biglycan; however, dermal fibroblasts from patients did not show consistent differences in β-catenin or p-SMAD2/3 nuclear abundance compared to controls. | Luciferase reporter assay in cell lines expressing mutant BGN, nuclear fractionation of patient fibroblasts | International journal of molecular sciences | Low | 41465473 |
| 2026 | HCN2 promotes nuclear translocation of the REST transcription factor, which binds the BGN promoter to transcriptionally activate BGN expression; BGN upregulation suppresses ferroptosis in bladder cancer cells, enhancing their proliferation and tumorigenesis. | Co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter assay, HCN2 knockdown in vitro and in vivo | International journal of molecular sciences | Medium | 42074076 |
| 2026 | In melanoma, BGN expression is regulated post-transcriptionally by m6A modification via YTHDF3, YTHDC1, and METTL14 acting in a parallel non-hierarchical manner; within the tumor microenvironment, CAF-derived BGN drives a BGN/MDK (midkine) axis that promotes CAF activation, melanoma proliferation/metastasis, and reduces CD8+ T cell infiltration. | Spatial transcriptomics, scRNA-seq, cell trajectory analysis, CellChat signaling analysis, AEBP1 regulatory assay, in vitro/in vivo functional assays | Advanced science | Low | 41833003 |
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 2019 | Mmu-miR-185 depletion promotes osteogenic differentiation and suppresses bone loss in osteoporosis through the Bgn-mediated BMP/Smad pathway. | Cell death & disease | 65 | 30787286 |
| 1990 | Localization of PGI (biglycan, BGN) and PGII (decorin, DCN, PG-40) genes on human chromosomes Xq13-qter and 12q, respectively. | Genomics | 60 | 1968422 |
| 2023 | BGN/FAP/STAT3 positive feedback loop mediated mutual interaction between tumor cells and mesothelial cells contributes to peritoneal metastasis of gastric cancer. | International journal of biological sciences | 50 | 36632455 |
| 1995 | The X-chromosomal human biglycan gene BGN is subject to X inactivation but is transcribed like an X-Y homologous gene. | Human genetics | 45 | 7607653 |
| 1992 | Fine mapping of the human biglycan (BGN) gene within the Xq28 region employing a hybrid cell panel. | Genomics | 45 | 1612609 |
| 2020 | BGN/TLR4/NF-B Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells. | Cells | 37 | 32050430 |
| 2015 | BgN-Score and BsN-Score: bagging and boosting based ensemble neural networks scoring functions for accurate binding affinity prediction of protein-ligand complexes. | BMC bioinformatics | 37 | 25734685 |
| 2016 | BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia. | American journal of human genetics | 33 | 27236923 |
| 2018 | The Influence of TGF-β3, EGF, and BGN on SOX9 and RUNX2 Expression in Human Chondrogenic Progenitor Cells. | The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society | 25 | 30431382 |
| 2015 | The small leucine-rich proteoglycan BGN accumulates in CADASIL and binds to NOTCH3. | Translational stroke research | 25 | 25578324 |
| 2022 | The lncRNA SEMA3B-AS1/HMGB1/FBXW7 Axis Mediates the Peritoneal Metastasis of Gastric Cancer by Regulating BGN Protein Ubiquitination. | Oxidative medicine and cellular longevity | 22 | 35273678 |
| 2024 | CLIC5 promotes myoblast differentiation and skeletal muscle regeneration via the BGN-mediated canonical Wnt/β-catenin signaling pathway. | Science advances | 19 | 39999205 |
| 2021 | LINC00460 Promotes Cell Proliferation, Migration, Invasion, and Epithelial-Mesenchymal Transition of Head and Neck Squamous Cell Carcinoma via miR-320a/BGN Axis. | OncoTargets and therapy | 17 | 33833526 |
| 2021 | lncRNA LINC00460 Functions as a Competing Endogenous RNA and Regulates Expression of BGN by Sponging miR-149-5p in Colorectal Cancer. | Technology in cancer research & treatment | 16 | 33472555 |
| 2020 | Silencing of miR-330-5p stimulates osteogenesis in bone marrow mesenchymal stem cells and inhibits bone loss in osteoporosis by activating Bgn-mediated BMP/Smad pathway. | European review for medical and pharmacological sciences | 16 | 32374006 |
| 2014 | The BGN and ACAN genes and carpal tunnel syndrome. | Gene | 15 | 25173489 |
| 2020 | PHF20 Promotes Glioblastoma Cell Malignancies Through a WISP1/BGN-Dependent Pathway. | Frontiers in oncology | 14 | 33117706 |
| 2023 | Long noncoding RNA ZEB1-AS1 attenuates ferroptosis of gastric cancer cells through modulating miR-429/BGN axis. | Journal of biochemical and molecular toxicology | 12 | 37128782 |
| 2020 | Consumer acceptability of acha and malted Bambara groundnut (BGN) biscuits sweetened with date palm. | Heliyon | 6 | 33294673 |
| 2024 | PDK1 promotes epithelial ovarian cancer progression by upregulating BGN. | Acta biochimica et biophysica Sinica | 5 | 39578715 |
| 2026 | Enhancer-mediated NR2F2 recruitment activates BGN to promote tumor growth and shape tumor microenvironment in papillary thyroid cancer. | Theranostics | 2 | 41328346 |
| 2025 | BGN Secreted by Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression via Activation of TLR4-Mediated Erk and NF-κB Signaling Pathways. | International journal of molecular sciences | 2 | 41465449 |
| 2023 | Corrigendum: PHF20 promotes glioblastoma cell malignancies through a WISP1/BGN-dependent pathway. | Frontiers in oncology | 2 | 37035210 |
| 2025 | Experience in Ceftazidime-Avibactam for treatment of MDR BGN infection in Oncologic Children. | The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases | 1 | 39985933 |
| 2025 | Study on the mechanism of BGN in progression and metastasis of ccRCC. | BMC medical genomics | 1 | 40108593 |
| 2025 | GLIS2 Promotes Epithelial-Mesenchymal Transition and Gastric Cancer Progression by Regulating BGN to Activate the Wnt/β-Catenin Pathway. | The Kaohsiung journal of medical sciences | 1 | 40936440 |
| 2026 | BGN/MDK Axis in the Melanoma Tumor Microenvironment Strengthens Tumor Malignancy by Modulating Cancer Cells and Cancer-Associated Fibroblasts Crosstalk. | Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 0 | 41833003 |
| 2026 | HCN2 Promotes BGN Transcription via REST to Regulate Ferroptosis and Tumor Progression in Bladder Cancer. | International journal of molecular sciences | 0 | 42074076 |
| 2025 | A Family with Meester-Loeys Syndrome Caused by a Novel Missense Variant in the BGN Gene. | International journal of molecular sciences | 0 | 41465473 |
| 2022 | Generation of an induced pluripotent stem cell (iPSC) line (BBANTWi009-A) from a Meester-Loeys syndrome patient carrying a BGN mutation. | Stem cell research | 0 | 36599284 |
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