Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress
Copyright policy )Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress
AbstractDespite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.
- National Institute of Health Pakistan
- Leibniz Association Germany
- Polish Academy of Sciences Poland
- Institute of Human Genetics France
- Leipzig University Germany
Antibiotics, Antineoplastic, Gene regulation, Chromatin and Epigenetics, Apoptosis, Cell Differentiation, Regulatory Factor X Transcription Factors, DNA, Prognosis, Signal Transduction ; Cell Line, Tumor [MeSH] ; Neoplasms/mortality [MeSH] ; Tumor Suppressor Protein p53/metabolism [MeSH] ; Genes, Tumor Suppressor [MeSH] ; Stress, Physiological/genetics [MeSH] ; Apoptosis [MeSH] ; Prognosis ; Mice ; Cell Differentiation/genetics ; Antibiotics, Antineoplastic/pharmacology [MeSH] ; Promoter Regions, Genetic ; Doxorubicin/pharmacology [MeSH] ; Transcriptome ; Regulatory Factor X Transcription Factors/metabolism ; Tumor Suppressor Protein p53/metabolism ; Regulatory Factor X Transcription Factors/physiology [MeSH] ; Gene Expression Regulation [MeSH] ; DNA/metabolism [MeSH] ; Regulatory Factor X Transcription Factors/physiology ; Trans-Activators/metabolism ; Humans ; Antibiotics, Antineoplastic/pharmacology ; Cell Line, Tumor ; Gene Expression Regulation ; Doxorubicin/pharmacology ; Neoplasms/genetics ; Regulatory Factor X Transcription Factors/metabolism [MeSH] ; Humans [MeSH] ; Cell Differentiation/genetics [MeSH] ; Apoptosis ; DNA/metabolism ; Neoplasms/genetics [MeSH] ; Animals [MeSH] ; Stress, Physiological/genetics ; Mice [MeSH] ; Gene Regulatory Networks [MeSH] ; Prognosis [MeSH] ; Signal Transduction [MeSH] ; Transcriptome [MeSH] ; Animals ; Neoplasms/mortality ; Genes, Tumor Suppressor ; Trans-Activators/metabolism [MeSH] ; Gene Regulatory Networks ; Promoter Regions, Genetic [MeSH], Mice, Gene Expression Regulation, Doxorubicin, Stress, Physiological, Cell Line, Tumor, Neoplasms, Trans-Activators, Animals, Humans, Gene Regulatory Networks, Genes, Tumor Suppressor, Promoter Regions, Genetic, Transcriptome, Signal Transduction
Antibiotics, Antineoplastic, Gene regulation, Chromatin and Epigenetics, Apoptosis, Cell Differentiation, Regulatory Factor X Transcription Factors, DNA, Prognosis, Signal Transduction ; Cell Line, Tumor [MeSH] ; Neoplasms/mortality [MeSH] ; Tumor Suppressor Protein p53/metabolism [MeSH] ; Genes, Tumor Suppressor [MeSH] ; Stress, Physiological/genetics [MeSH] ; Apoptosis [MeSH] ; Prognosis ; Mice ; Cell Differentiation/genetics ; Antibiotics, Antineoplastic/pharmacology [MeSH] ; Promoter Regions, Genetic ; Doxorubicin/pharmacology [MeSH] ; Transcriptome ; Regulatory Factor X Transcription Factors/metabolism ; Tumor Suppressor Protein p53/metabolism ; Regulatory Factor X Transcription Factors/physiology [MeSH] ; Gene Expression Regulation [MeSH] ; DNA/metabolism [MeSH] ; Regulatory Factor X Transcription Factors/physiology ; Trans-Activators/metabolism ; Humans ; Antibiotics, Antineoplastic/pharmacology ; Cell Line, Tumor ; Gene Expression Regulation ; Doxorubicin/pharmacology ; Neoplasms/genetics ; Regulatory Factor X Transcription Factors/metabolism [MeSH] ; Humans [MeSH] ; Cell Differentiation/genetics [MeSH] ; Apoptosis ; DNA/metabolism ; Neoplasms/genetics [MeSH] ; Animals [MeSH] ; Stress, Physiological/genetics ; Mice [MeSH] ; Gene Regulatory Networks [MeSH] ; Prognosis [MeSH] ; Signal Transduction [MeSH] ; Transcriptome [MeSH] ; Animals ; Neoplasms/mortality ; Genes, Tumor Suppressor ; Trans-Activators/metabolism [MeSH] ; Gene Regulatory Networks ; Promoter Regions, Genetic [MeSH], Mice, Gene Expression Regulation, Doxorubicin, Stress, Physiological, Cell Line, Tumor, Neoplasms, Trans-Activators, Animals, Humans, Gene Regulatory Networks, Genes, Tumor Suppressor, Promoter Regions, Genetic, Transcriptome, Signal Transduction
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