3, 3′5 Triiodo L Thyronine Induces Apoptosis in Human Breast Cancer MCF-7cells, Repressing SMP30 Expression through Negative Thyroid Response Elements

Abstract

BackgroundThyroid 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 (T3), represses SMP30 in rat liver.Methodology/Principal FindingsIn 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.ConclusionThis 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.

Histone acetylation inhibitors promote axon growth in adult dorsal root ganglia neurons

“…CPTH2 is an inhibitor of the HAT Gcn5 in cancer cells (Sar et al, ), but it has never been tested in neuronal cultures. In neurons treated with CPTH2, the mean length of the longest axon peaked in cultures treated with 50 nM (252.9 ± 40 μm) and progressively declined with higher concentrations (Fig.…”

Thyroid Hormone Signaling and Cone Photoreceptor Viability

“…Excessive TH signaling induces auditory defects (Ng et al 2009b), causes cerebellar abnormalities (Peeters et al 2013), and is associated with apoptosis of a variety of human cell lines, including lymphocytes (Mihara et al 1999), breast cancer cells (Sar et al 2011), and pituitary tumor cells (Chiloeches et al 2008). In addition, TR signaling has been well documented in apoptotic tissue remodeling during anuran metamorphosis (Shi et al 2001;Buchholz et al 2004).…”

“…Stimulating TH signaling induces degeneration of rods (Ng et al 2010;Ma et al 2014) and cochlear hair cells (Ng et al 2009b), which do not express cone opsin. Moreover, TH signaling induces death in numerous cancer cell lines (Yamada-Okabe et al 2003;Chiloeches et al 2008;Sar et al 2011).…”

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

“…Excessive TH signaling was also shown to induce auditory defects and cochlear degeneration in mice (13). TH signaling has been associated with apoptosis of a variety of human cell lines, including lymphocytes (14), breast cancer cells (15), HeLa cells (16), and pituitary tumor cells (17), and TH signaling has been well documented in apoptotic tissue remodeling during anuran metamorphosis (18,19). To determine whether TH signaling affects cone viability in inherited retinal degeneration, we investigated cone death/survival in retinal degeneration mouse models following TH signaling suppression and stimulation.…”