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A novel transcription factor SIPA1: identification and verification in triple-negative breast cancer
Lijuan Guo1, Wanjun Zhang1, Xue Zhang2
1Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
Abstract:
Transcription factors (TFs) regulate the expression of genes responsible for cell growth, differentiation, and responses to environmental factors. In this study, we demonstrated that signal-induced proliferation-associated 1 (SIPA1), known as a Rap-GTPase-activating protein, bound DNA and served as a TF. Importin β1 was found to interact with SIPA1 upon fibronectin treatment. A TGAGTCAB motif was recognized and bound by DNA-binding region (DBR) of SIPA1, which was confirmed by electrophoretic mobility shift assay. SIPA1 regulated the transcription of multiple genes responsible for signal transduction, DNA synthesis, cell adhesion, cell migration, and so on. Transcription of fibronectin 1, which is crucial for cell junction and migration of triple-negative breast cancer (TNBC) cells, was regulated by SIPA1 in a DBR-dependent manner both in vivo and in vitro. Furthermore, single-cell transcriptome sequencing analysis of specimens from a metastatic TNBC patient revealed that SIPA1 was highly expressed in metastatic TNBC. Hence, this study demonstrated that SIPA1 served as a TF, promoting TNBC migration, invasion, and metastasis.
Insights
Signal-induced proliferation-associated 1 (SIPA1) functions as a transcription factor, regulating genes involved in cell processes. SIPA1 promotes triple-negative breast cancer (TNBC) migration and metastasis.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Transcription factors (TFs) are crucial regulators of cellular processes.
- Signal-induced proliferation-associated 1 (SIPA1) is known as a Rap-GTPase-activating protein.
- The role of SIPA1 as a TF and its involvement in cancer metastasis were not fully understood.
Purpose of the Study:
- To investigate the role of SIPA1 as a DNA-binding protein and transcription factor.
- To elucidate the mechanism by which SIPA1 influences gene expression.
- To determine the involvement of SIPA1 in the migration, invasion, and metastasis of triple-negative breast cancer (TNBC).
Main Methods:
- Electrophoretic mobility shift assay (EMSA) to confirm DNA binding.
- Analysis of SIPA1-DNA interactions using its DNA-binding region (DBR).
- Single-cell transcriptome sequencing of metastatic TNBC patient specimens.
Main Results:
- SIPA1 was identified as a DNA-binding protein that functions as a TF.
- SIPA1 binds to the TGAGTCAB motif via its DBR.
- SIPA1 regulates genes involved in cell signaling, DNA synthesis, adhesion, and migration.
- SIPA1 transcriptionally upregulates fibronectin 1, promoting TNBC cell migration and junction formation.
- SIPA1 is highly expressed in metastatic TNBC and promotes cancer cell migration, invasion, and metastasis.
Conclusions:
- SIPA1 acts as a transcription factor, regulating key cellular processes.
- SIPA1 plays a significant role in promoting TNBC cell migration, invasion, and metastasis.
- Targeting SIPA1 may offer a therapeutic strategy for metastatic TNBC.
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