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3, 3'5 Triiodo L thyronine induces apoptosis in human breast cancer MCF-7 cells, repressing SMP30 expression through
Pranati Sar1, Rosalima Peter, Bandita Rath
1Cancer Biology Lab, Department of Gene Function and Regulation, Institute of Life Sciences, Chandrasekharpur, Bhubaneswar, India.
Background:
Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3'5 Triiodo L Thyronine (T(3)), represses SMP30 in rat liver.
Methodology/Principal Findings:
In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRβ, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions.
Conclusion:
This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer.
Insights
Thyroid hormone (T3) represses Senescence Marker Protein-30 (SMP30) expression, inducing apoptosis in human breast cancer cells. This novel mechanism offers potential therapeutic targets for breast cancer treatment.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Thyroid hormones are crucial regulators of cell proliferation, differentiation, and apoptosis.
- The precise molecular mechanisms by which thyroid hormone signaling induces apoptosis remain incompletely understood.
- Senescence Marker Protein-30 (SMP30) exhibits antiapoptotic properties, and its regulation by thyroid hormone is a focus of investigation.
Purpose of the Study:
- To elucidate the molecular mechanism by which thyroid hormone (T3) regulates SMP30 expression and induces apoptosis in human breast cancer cells.
- To investigate the role of SMP30 in mediating thyroid hormone-induced apoptosis.
- To identify cis-acting elements and epigenetic modifications involved in thyroid hormone-mediated regulation of the SMP30 gene.
Main Methods:
- Utilized MCF-7 human breast cancer cell line.
- Administered T3 treatment and analyzed SMP30 expression and apoptosis via flow cytometry.
- Constructed and analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors.
- Employed siRNA-mediated silencing of Thyroid Hormone Receptor beta (TRβ) and Trichostatin A (TSA) treatment.
Main Results:
- T3 treatment repressed SMP30 expression, leading to enhanced apoptosis in MCF-7 cells.
- Overexpression of SMP30 decelerated apoptosis, while silencing accelerated it.
- Thyroid hormone down-regulated hSMP30 promoter activity, identifying specific thyroid response elements (TREs) as negative regulatory elements.
- Silencing of TRβ reduced the repression of SMP30 gene expression, and TSA further inhibited promoter activity in the presence of T3.
Conclusions:
- This study reveals a novel mechanism of SMP30 gene downregulation by thyroid hormone, which consequently induces apoptosis in human breast cancer cells.
- Identified specific TREs within the hSMP30 promoter that act as negative response elements.
- The findings provide a foundation for developing new therapeutic strategies against breast cancer progression.
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