KCTD11 Human
Description
Introduction to KCTD11 Human
KCTD11 (Potassium Channel Tetramerization Domain Containing 11) is a protein-coding gene located on chromosome 17q25.3 in humans. It belongs to the KCTD family, characterized by a conserved N-terminal BTB/POZ domain involved in protein-protein interactions and a variable C-terminal region . KCTD11 is widely expressed in tissues such as the brain, thyroid gland, adrenal gland, and gastrointestinal tract, with moderate levels in the liver, lungs, and kidneys .
Molecular Mechanisms and Functional Roles
KCTD11 acts as a tumor suppressor through its interaction with key signaling pathways:
Key Pathways and Targets
In lung cancer, KCTD11 overexpression reduces β-catenin-dependent transcription by 60–70% and inhibits YAP nuclear accumulation, correlating with improved patient survival .
Lung Cancer
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Clinical Data: Low KCTD11 expression correlates with advanced TNM stage (p < 0.01), lymph node metastasis (p < 0.05), and poor 5-year survival (35% vs. 68% in high-expression groups) .
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Functional Impact:
Hepatocellular Carcinoma (HCC)
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Expression: Downregulated in 82% of HCC tissues compared to adjacent normal liver .
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Therapeutic Effects:
Regulatory Interactions
KCTD11 expression is modulated by environmental and pharmacological factors:
| Modulator | Effect on KCTD11 Expression | Source |
|---|---|---|
| Cisplatin | Increased | |
| Valproic Acid | Decreased | |
| Benzo[a]pyrene | Alters promoter methylation | |
| β-Lapachone | Increased |
Clinical and Prognostic Significance
Future Directions
Product Specs
Q&A
How is KCTD11 expression quantified in human tissues, and what validation methods ensure reliability?
KCTD11 expression analysis employs immunohistochemistry (IHC) with polyclonal antibodies (1:100–1:500 dilution) validated for specificity in formalin-fixed paraffin-embedded (FFPE) tissues . Scoring integrates staining intensity (0–3 scale) and positive cell proportion (1–4 scale), with a composite score ≥4 indicating high expression . For mRNA quantification, qRT-PCR using SYBR® Green or TaqMan probes (e.g., Hs00628328_s1 for KCTD11) normalized to GAPDH or HPRT ensures precision . Western blotting with anti-KCTD11 antibodies (e.g., Sigma HPA052035) at 1:1000 dilution confirms protein levels, though epitope masking in FFPE samples may necessitate antigen retrieval .
What functional roles does KCTD11 play in cancer pathogenesis?
KCTD11 suppresses tumor growth via:
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Cell cycle arrest: Upregulation of p21 and inhibition of cyclin-dependent kinases (CDK2, CDK4) in HCC .
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Metastasis suppression: Downregulation of matrix metalloproteinases (MMP2, MMP9) and epithelial-mesenchymal transition (EMT) markers (Snail, Vimentin) .
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Pathway modulation: Activation of Hippo signaling (MST1/GSK3β/p21 axis) and inhibition of β-catenin/TCF4 transcriptional activity in non-small cell lung cancer (NSCLC) .
Which interaction partners and pathways are central to KCTD11’s tumor-suppressive function?
KCTD11 binds β-catenin via its BTB domain, sequestering it from the nucleus and suppressing Wnt target genes (e.g., CCND1, MYC) . In SHH-medulloblastoma, KCTD11 forms the CRL3REN E3 ligase complex, promoting degradation of SALL4, a transcriptional activator of SHH signaling . Hippo pathway activation via MST1 kinase phosphorylation is another key mechanism .
How do researchers reconcile contradictory data on KCTD11’s context-dependent roles?
Discrepancies arise from tissue-specific signaling crosstalk. For example:
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Prognostic value: Low KCTD11 correlates with poor HCC survival (HR = 2.1, p < 0.01) , yet in SHH-medulloblastoma, KCTD11 mRNA does not predict outcomes (log-rank p = 0.32) .
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Pathway antagonism: KCTD11 inhibits Wnt/β-catenin in NSCLC but enhances Hippo signaling in HCC. Tissue-specific cofactors (e.g., YAP1 in HCC) may explain differential effects .
Methodological resolution: -
Perform multi-omics profiling (RNA-seq, ChIP-seq) to map KCTD11 interactomes across cancer types.
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Use isogenic cell lines with KCTD11 knockout to isolate pathway-specific effects.
How can KCTD11 be therapeutically targeted given its dual role in protein stability and transcriptional regulation?
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PROTAC degradation: Design bifunctional molecules linking KCTD11 binders to E3 ligases (e.g., VHL) to enhance SALL4 degradation in SHH tumors .
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Small-molecule agonists: High-throughput screening identified NSC-658497 as a KCTD11 stabilizer (EC50 = 1.2 μM), augmenting β-catenin binding in NSCLC .
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Gene therapy: Adenovirus-mediated KCTD11 delivery (MOI = 10) reduces HCC metastasis in murine models by 70% .
Table 1: KCTD11 Expression and Clinical Outcomes in HCC
| Study Cohort (n) | Expression Level | 5-Year Survival | Hazard Ratio (95% CI) |
|---|---|---|---|
| Low KCTD11 (45) | IHC score ≤ 3 | 22% | 2.1 (1.3–3.4) |
| High KCTD11 (38) | IHC score ≥ 4 | 58% | Reference |
| Source: |
Table 2: KCTD11-Dependent Pathway Modulation
Methodological Best Practices
Product Science Overview
KCTD11 is a protein-coding gene that produces a protein involved in several important cellular processes. The protein contains a BTB/POZ domain, which is known for its role in protein-protein interactions . This domain is crucial for the tetramerisation of potassium channels, which are essential for maintaining the electrical excitability of cells .
The KCTD11 protein is involved in the regulation of neuronal differentiation and has been shown to induce apoptosis (programmed cell death), growth arrest, and the expression of cyclin-dependent kinase inhibitor CDKN1B . It acts as a tumor suppressor and inhibits the growth and tumorigenicity of medulloblastoma, a type of brain cancer .
KCTD11 is upregulated by various neurogenic signals, such as retinoic acid, epidermal growth factor (EGF), and nerve growth factor (NGF) . It functions as an antagonist of the Hedgehog signaling pathway, which is involved in cell proliferation and differentiation . By affecting the nuclear transfer of the transcription factor GLI1, KCTD11 helps maintain cerebellar granule cells in an undifferentiated state .
Additionally, KCTD11 is a probable substrate-specific adapter for a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex towards HDAC1 . This interaction is significant for the regulation of protein degradation and cellular homeostasis.
Recombinant KCTD11 is produced using Escherichia coli (E. coli) expression systems. The recombinant protein is typically a non-glycosylated polypeptide chain containing 252 amino acids and has a molecular mass of approximately 28 kDa . It is often fused to a His-tag at the N-terminus to facilitate purification using chromatographic techniques .
Recombinant KCTD11 is used in various research applications, including studies on protein-protein interactions, signal transduction pathways, and the development of potential therapeutic agents targeting the Hedgehog signaling pathway .
