Abstract
BackgroundSin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin3 repressive complex. It functions as a scaffold upon which proteins with enzymatic activity dock, including chromatin modifying histone deacetylases. Although regulation of transcription by Sin3A has been studied in detail, little is understood about the function of Sin3A in cancer cells. We previously showed that Sin3A is expressed in breast cancer cells and is a repressor of estrogen receptor-alpha (ERα, ESR1) gene expression. Here, we expand our previous studies to elucidate the function of Sin3A in the control of gene expression and growth of breast cancer cells.ResultsAnalysis of gene expression following knockdown of Sin3A revealed changes in both basal and regulated gene transcription. Genes of known importance in breast cancer and estrogen signaling, including ERBB2, PGR, MYC, CLU, and NCOA2, were among those identified as Sin3A-responsive. The mechanism of Sin3A action varied among genes and was found to be mediated through both HDAC1/2 -dependent and -independent activities. Loss of Sin3A inhibited breast cancer cell growth by increasing apoptosis without affecting cell cycle progression. Analysis of both ERα-positive and ERα-negative cell lines revealed that the effects of Sin3A on growth were cell-type specific, as Sin3A expression promoted maximum growth of only the ERα-positive cells, and, notably, Sin3A protein itself was increased by estrogen. Further gene expression experiments revealed that Sin3A repressed expression of key apoptotic genes, including TRAIL, TRAILR1, CASP10, and APAF1, in ERα-positive, but not ERα-negative, cell lines, which could provide a mechanistic explanation for cell-type differences in growth.ConclusionsThis study identifies Sin3A as a regulator of gene expression, survival, and growth in ERα-positive breast cancer cells. Sin3A regulates the transcription of genes involved in breast cancer and apoptosis and acts through multiple mechanisms not limited to histone deacetylase function. These findings reveal previously undescribed functions of Sin3A in breast cancer and provide evidence for an important role of this transcriptional repressor in ERα-positive tumor cell growth.
Highlights
Sin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin3 repressive complex
Our lab previously showed that Sin3A regulated the estrogeninduced repression of the estrogen receptor-alpha (ERa) gene, ESR1, in the MCF7 breast cancer cell line [9]
Knockdown of Sin3A protein and mRNA by Sin3A siRNA were validated by western blot and quantitative reverse transcriptase realtime PCR, respectively (Figure 1A and 1B; the band for the Sin3A protein at the molecular weight of 145 kDa is marked with an asterisk)
Summary
Sin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin repressive complex. Microarray analyses on estrogen-treated breast cancer cells show that the number of repressed genes is greater than or near the number of activated genes [5,6,7,8]. These experiments show that estrogen-mediated repression of genes is clearly biologically important, the mechanisms responsible for repression are not fully understood. We previously showed that the Sin3A transcriptional repressor protein is a regulator of estrogen-induced repression of the ERa gene, ESR1, in breast cancer cells [9]. These data suggested that Sin3A may play a broader role in ERapositive breast cancer cells
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