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Published on: March 27, 2020
Tumor suppressor SMAR1 represses IkappaBalpha expression and inhibits p65 transactivation through matrix attachment
Kamini Singh1, Surajit Sinha, Sunil Kumar Malonia
1National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, Maharastra, India.
Abstract:
Aberrant NF-kappaB activity promotes tumorigenesis. However, NF-kappaB also inhibits tumor growth where tumor suppressor pathways remain unaltered. Thus, its role in tumorigenesis depends upon the function of other cellular factors. Tumor suppressor SMAR1 down-modulated in high grade breast cancers is regulated by p53 and is reported to interact and stabilize p53. Because both SMAR1 and NF-kappaB are involved in tumorigenesis, we investigated the effect of SMAR1 upon NF-kappaB activity. We show that SMAR1 induction by doxorubicin or overexpression produces functional NF-kappaB complexes that are competent for binding to NF-kappaB consensus sequence. However, SMAR1 induced p65-p50 complex is phosphorylation- and transactivation-deficient. Induction of functional NF-kappaB complexes stems from down-regulation of IkappaBalpha transcription through direct binding of SMAR1 to the matrix attachment region site present in IkappaBalpha promoter and recruitment of corepressor complex. Real time PCR array for NF-kappaB target genes revealed that SMAR1 down-regulates a subset of NF-kappaB target genes that are involved in tumorigenesis. We also show that SMAR1 inhibits tumor necrosis factor alpha-induced induction of NF-kappaB suggesting that activation of NF-kappaB by SMAR1 is independent and different from classical pathway. Thus, for the first time we report that a tumor suppressor protein SMAR1 can modulate NF-kappaB transactivation and inhibit tumorigenesis by regulating NF-kappaB target genes.
Insights
The tumor suppressor SMAR1 modulates nuclear factor-kappa B (NF-kappaB) activity, inhibiting tumorigenesis by regulating NF-kappaB target genes. This study reveals SMAR1
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Aberrant nuclear factor-kappa B (NF-kappaB) activity is implicated in tumorigenesis.
- The tumor suppressor SMAR1, downregulated in breast cancer, interacts with p53.
- The precise role of NF-kappaB in tumorigenesis is context-dependent.
Purpose of the Study:
- To investigate the effect of the tumor suppressor SMAR1 on NF-kappaB activity.
- To elucidate the mechanism by which SMAR1 influences NF-kappaB.
- To determine if SMAR1 can modulate NF-kappaB-driven tumorigenesis.
Main Methods:
- SMAR1 induction via doxorubicin or overexpression.
- Analysis of NF-kappaB complex formation and DNA binding.
- Investigation of IkappaBalpha promoter activity and transcription.
- Real-time PCR array to assess NF-kappaB target gene expression.
- Assessment of SMAR1's effect on TNF-alpha-induced NF-kappaB activation.
Main Results:
- SMAR1 induction generates functional NF-kappaB complexes that bind DNA.
- SMAR1-induced NF-kappaB complexes are deficient in phosphorylation and transactivation.
- SMAR1 downregulates IkappaBalpha transcription by binding to its promoter and recruiting corepressors.
- SMAR1 downregulates a subset of tumorigenic NF-kappaB target genes.
- SMAR1 inhibits TNF-alpha-induced NF-kappaB activation, suggesting a non-classical pathway.
Conclusions:
- SMAR1 modulates NF-kappaB transactivation, distinct from the classical pathway.
- SMAR1 inhibits tumorigenesis by regulating specific NF-kappaB target genes.
- This study identifies SMAR1 as a novel regulator of NF-kappaB in cancer.
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