GTF3C6 Human

What is GTF3C6 and what is its primary function?

GTF3C6 (General Transcription Factor IIIC Subunit 6) is a protein-coding gene located on chromosome 6 in humans . It encodes a 213-amino acid protein that functions as an integral component of the DNA-binding TFIIIC2 subcomplex . The primary function of GTF3C6 is involvement in RNA polymerase III-mediated transcription, where it plays a crucial role in the transcription of RNA polymerase III-dependent genes . Specifically, it is part of the TFIIIC complex that directly binds tRNA and virus-associated RNA promoters .

What are the alternative names and identifiers for GTF3C6?

GTF3C6 is known by several alternative names in scientific literature and databases:

These alternative designations appear in various databases and publications, making it important for researchers to recognize all nomenclature when conducting literature searches .

How does GTF3C6 contribute to cancer development, particularly in lung adenocarcinoma?

Recent research has revealed that GTF3C6 plays a significant role in lung adenocarcinoma (LUAD) progression . GTF3C6 is highly expressed in LUAD tissues, LUAD mouse models (LSL-Kras G12D/+;LSL-p53 -/- genotype), and patient-derived LUAD organoids . This elevated expression correlates with poor clinical prognosis in LUAD patients .

Mechanistically, GTF3C6 promotes several hallmarks of cancer including:

• Anchorage-independent proliferation of LUAD cells

• Enhanced migration capabilities

• Increased invasive properties

• Tumor growth in vivo

These findings suggest that GTF3C6 functions as an oncogenic factor in LUAD and potentially other cancer types .

What signaling pathways regulate GTF3C6 expression and function in cancer?

Research has identified a critical regulatory axis involving KRAS mutations, PI3K signaling, and GTF3C6 in lung adenocarcinoma :

• Upstream regulation: KRAS mutations drive GTF3C6 expression through the PI3K pathway in LUAD cells.

• Downstream effects: GTF3C6 promotes cancer progression by regulating FAK (Focal Adhesion Kinase) phosphorylation.

This signaling cascade is particularly significant because:

• KRAS mutations are common driver mutations in LUAD but have historically been difficult to target therapeutically

• The identification of GTF3C6 as a downstream effector of KRAS/PI3K signaling presents a potential alternative therapeutic strategy

• Knockdown of GTF3C6 has been shown to reverse the malignant phenotype of KRAS mutation-driven LUAD cells

This suggests that targeting GTF3C6 might be an effective approach for treating KRAS-driven cancers, which have traditionally been challenging to address with direct KRAS inhibitors .

What experimental approaches are most effective for studying GTF3C6 function?

Based on published research methodologies, several experimental approaches have proven effective for investigating GTF3C6:

Protein Expression Analysis:

• Western blot analysis using validated GTF3C6 antibodies

• Immunohistochemistry (IHC) for tissue samples

• Immunofluorescence for cellular localization studies

Transcriptional Analysis:

• Quantitative real-time PCR (qRT-PCR) for mRNA expression levels

Functional Studies:

• Gene knockdown via siRNA or shRNA approaches

• CRISPR-Cas9 mediated gene editing

• Organoid formation assays to assess three-dimensional growth properties

• In vivo xenograft models for tumor growth assessment

Protein-Protein Interaction Studies:

• Co-immunoprecipitation to identify binding partners

• Chromatin immunoprecipitation (ChIP) to map genomic binding sites

Researchers should select methodologies based on their specific research questions, keeping in mind that combining multiple approaches will provide more robust insights into GTF3C6 function .

How does GTF3C6 compare with other members of the GTF3 family in cancer research?

The GTF3 family includes several members that have been studied in cancer contexts, particularly in colorectal cancer (CRC). Research findings indicate distinct expression patterns and prognostic implications:

• GTF3A: Shows higher expression in CRC tissues compared to normal tissues at both mRNA and protein levels. Higher expression of GTF3A correlates with poor prognosis in CRC patients (Disease-specific survival hazard ratio = 1.48) .

• GTF3B: Exhibits lower expression in CRC tissues compared to normal tissues. Expression of GTF3B is associated with better prognosis in CRC (Disease-specific survival hazard ratio = 0.30) .

• GTF3C1: Shows lower expression in CRC tissues than in normal tissues, but protein levels were reported to be higher in CRC tissues based on immunohistochemistry analysis .

• GTF3C2: Demonstrates lower expression in CRC tissues compared to normal tissues. Expression correlates with better prognosis in CRC (Disease-specific survival hazard ratio = 0.24) .

• GTF3C6: In contrast to the above family members studied in CRC, GTF3C6 has been primarily investigated in lung adenocarcinoma, where it shows higher expression in cancer tissues and promotes malignant phenotypes .

These findings suggest that different members of the GTF3 family may play distinct, and sometimes opposing, roles in cancer progression, highlighting the importance of studying each family member specifically in different cancer types .

What are the implications of GTF3C6 as a potential therapeutic target?

GTF3C6 presents several characteristics that make it a promising therapeutic target, particularly in KRAS-driven cancers:

• Downstream effector of KRAS: As a downstream target of KRAS/PI3K signaling, GTF3C6 offers an alternative approach to targeting KRAS-driven cancers, which have proven challenging to address directly .

• Functional significance: GTF3C6 knockdown experiments have demonstrated significant inhibition of:

  • LUAD organoid formation

  • Tumor growth in vivo

  • Malignant phenotypes including proliferation, migration, and invasion

• Potential biomarker: High expression of GTF3C6 correlates with poor clinical prognosis, suggesting its utility as a prognostic biomarker .

• Pathway specificity: The involvement of GTF3C6 in regulating FAK phosphorylation provides an opportunity for targeted intervention in cancer-specific signaling processes .

Therapeutic strategies might include:

• Development of small molecule inhibitors that disrupt GTF3C6 function

• RNA interference approaches to reduce GTF3C6 expression

• Blocking the interaction between GTF3C6 and its key binding partners

What experimental models are available for studying GTF3C6?

Several experimental models have been validated for GTF3C6 research:

Cellular Models:

• Human LUAD cell lines (various KRAS mutation statuses)

• Normal lung epithelial cell lines (as controls)

• Cell lines with genetic manipulations of GTF3C6 (knockdown or overexpression)

Animal Models:

• LSL-Kras G12D/+;LSL-p53 -/- genetically engineered mouse model of LUAD

• Xenograft models using cell lines with manipulated GTF3C6 expression

Three-dimensional Models:

• Patient-derived LUAD organoids, which provide a more physiologically relevant system than traditional 2D cell culture

• These organoids maintain many of the molecular and phenotypic features of the original tumors

Comparative Models:

• Zebrafish gtf3c6 ortholog studies provide evolutionary insights

• The zebrafish gtf3c6 gene is predicted to have similar functions in transcription by RNA polymerase III

The choice of model system should align with specific research questions, with consideration for species differences, tissue context, and experimental limitations.

How can researchers effectively detect and quantify GTF3C6 expression?

Multiple validated methods exist for detecting and quantifying GTF3C6 at both RNA and protein levels:

RNA-Level Detection:

• qRT-PCR: Allows for precise quantification of GTF3C6 mRNA expression

• RNA-seq: Provides comprehensive transcriptome analysis and can identify splice variants

• Northern blot: Though less common now, can be used for size verification of transcripts

Protein-Level Detection:

• Western blot: Using validated GTF3C6-specific antibodies

• Immunohistochemistry (IHC): For detection in tissue sections

• Immunofluorescence (IF): For subcellular localization studies

• Mass spectrometry: For detailed protein characterization and post-translational modification analysis

For recombinant GTF3C6 protein work, the literature indicates successful expression in E. coli systems with >85% purity, making the protein suitable for use in SDS-PAGE and mass spectrometry applications .

When selecting detection methods, researchers should consider sensitivity requirements, sample availability, and whether relative or absolute quantification is needed for their specific research goals.

What are the challenges in studying GTF3C6 and how can they be addressed?

Researchers face several challenges when investigating GTF3C6:

• Antibody specificity: As with many transcription factors, developing highly specific antibodies can be challenging. Researchers should validate antibodies using appropriate controls, including:

  • GTF3C6 knockdown/knockout samples

  • Recombinant GTF3C6 protein as a positive control

  • Testing multiple antibodies targeting different epitopes

• Functional redundancy: As part of the GTF3 family, there may be functional overlap with other family members. Address this by:

  • Performing comprehensive family member expression profiling

  • Using combinatorial knockdown approaches

  • Conducting rescue experiments with specific family members

• Context-dependent effects: GTF3C6 may function differently depending on cell type, tissue context, or disease state. Researchers should:

  • Study GTF3C6 across multiple cell types and contexts

  • Use patient-derived models when possible

  • Consider three-dimensional culture systems that better recapitulate in vivo conditions

• Mechanistic complexity: As a transcription factor component, GTF3C6 likely affects multiple downstream targets. To address this complexity:

  • Perform global transcriptomic and proteomic analyses following GTF3C6 manipulation

  • Use chromatin immunoprecipitation followed by sequencing (ChIP-seq) to identify genomic binding sites

  • Apply network analysis to identify key regulatory nodes

• Translational relevance: Bridging basic science findings to clinical applications requires careful validation. Researchers should:

  • Analyze GTF3C6 expression in large patient cohorts

  • Correlate expression with clinical outcomes

  • Validate findings across multiple independent datasets

By anticipating and systematically addressing these challenges, researchers can develop more robust and translatable insights into GTF3C6 biology.

What are the current gaps in GTF3C6 research?

Despite recent advances in understanding GTF3C6 function, particularly in the context of lung adenocarcinoma, several significant knowledge gaps remain:

• Comprehensive cancer profiling: While GTF3C6 has been studied in LUAD, its expression patterns and functional roles across other cancer types remain largely unexplored. The GTF3 family shows varying expression patterns in colorectal cancer, suggesting potential cancer-specific roles for GTF3C6 .

• Normal tissue function: The physiological role of GTF3C6 in healthy tissues is not well characterized, creating challenges for predicting potential side effects of therapeutic targeting.

• Structural biology: Detailed structural information about GTF3C6 protein, including crystal structures and domain-specific functions, would facilitate structure-based drug design efforts.

• Regulatory mechanisms: Beyond KRAS/PI3K signaling in LUAD, other upstream regulators of GTF3C6 expression and activity remain to be identified across different cellular contexts.

• Downstream targets: The complete set of genes and pathways regulated by GTF3C6 as part of the TFIIIC complex requires further characterization.

Addressing these knowledge gaps would significantly advance our understanding of GTF3C6 biology and its potential as a therapeutic target.

How might GTF3C6 research evolve in the coming years?

Based on current trends and emerging technologies, GTF3C6 research is likely to evolve in several directions:

• Single-cell approaches: Application of single-cell transcriptomics and proteomics will reveal cell-type specific roles of GTF3C6 and potential heterogeneity in its expression and function within tumors.

• CRISPR-based functional genomics: Genome-wide CRISPR screens may identify synthetic lethal interactions with GTF3C6, revealing potential combination therapy opportunities.

• Patient-derived models: Increased use of patient-derived organoids and xenografts will provide more physiologically relevant systems for testing GTF3C6-targeted interventions.

• Computational approaches: Integration of multi-omics data using machine learning approaches will help predict patient populations most likely to benefit from GTF3C6-targeted therapies.

• Development of targeted therapeutics: Following the emerging evidence of GTF3C6's role in cancer, particularly KRAS-driven malignancies, efforts to develop specific inhibitors or degraders of GTF3C6 may accelerate.

As research progresses, GTF3C6 may emerge as an important component in precision medicine approaches, particularly for cancers with limited treatment options such as KRAS-mutant lung adenocarcinoma .