Abstract
The eukaryotic cell cycle is controlled by a complex regulatory network, which is still poorly understood. Here we demonstrate that TRPS1, an atypical GATA factor, modulates cell proliferation and controls cell cycle progression. Silencing TRPS1 had a differential effect on the expression of nine key cell cycle-related genes. Eight of these genes are known to be involved in the regulation of the G2 phase and the G2/M transition of the cell cycle. Using cell synchronization studies, we confirmed that TRPS1 plays an important role in the control of cells in these phases of the cell cycle. We also show that silencing TRPS1 controls the expression of 53BP1, but not TP53. TRPS1 silencing also decreases the expression of two histone deacetylases, HDAC2 and HDAC4, as well as the overall HDAC activity in the cells, and leads to the subsequent increase in the acetylation of histone4 K16 but not of histone3 K9 or K18. Finally, we demonstrate that TRPS1 expression is elevated in luminal breast cancer cells and luminal breast cancer tissues as compared with other breast cancer subtypes. Overall, our study proposes that TRPS1 acts as a central hub in the control of cell cycle and proliferation during cancer development.
Highlights
Cells proliferate rapidly during embryonic and postnatal development,[1] and studies show that deregulation of proliferation and a reduction in the degree of apoptosis are necessary steps in cancer initiation and progression.[2]
TRPS1 was previously linked to apoptosis of prostate cancer cells[13, 29, 45] and chondrocytes,[22] we found that TRPS1 silencing had little effect on BT474 cell apoptosis (Figure 1D)
[51] the mechanism(s) governing cell cycle transitions is central in the study of cell proliferation[3] and it is presumed that aberrations to this cell cycle control are partly responsible for the onset and development of tumor
Summary
Cells proliferate rapidly during embryonic and postnatal development,[1] and studies show that deregulation of proliferation and a reduction in the degree of apoptosis are necessary steps in cancer initiation and progression.[2]. TRPS1 is an atypical GATA protein containing three distinct zinc finger domains, C2H2, GATA, and Ikaros, which bind to GATA sequences and regulate gene expression by repressing the transcriptional activation of other GATA factors. Transcriptional repression by TRPS1 depends on the modulation of its C-terminal repressor region (RG) through SUMOylation[12]—rather than through www.impactjournals.com/oncotarget competition for DNA binding[13, 14]—and studies show that TRPS1 is directly inhibited by the dynein light chain 8 protein (LC8a) and RING finger protein 4 (RNF4).[15] Besides repressing transcription, TRPS1 was contrarily found to activate the transcription of Wnt inhibitors, such as Wif, Apcdd and Dkk in the developing vibrissa follicle, by directly binding to their promoters.[16]
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