A central role for TRPS1 in the control of cell cycle and cancer development

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.

[1]  S. Cohen,et al.  Connecting proliferation and apoptosis in development and disease , 2004, Nature Reviews Molecular Cell Biology.

[2]  R. Shivdasani,et al.  Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome. , 2008, Human molecular genetics.

[3]  Y. Muragaki,et al.  Trps1 haploinsufficiency promotes renal fibrosis by increasing Arkadia expression. , 2010, Journal of the American Society of Nephrology : JASN.

[4]  R. Patient,et al.  GATA-1 DNA Binding Activity Is Down-regulated in Late S Phase in Erythroid Cells* , 1997, The Journal of Biological Chemistry.

[5]  J. McGhee,et al.  The GATA family (vertebrates and invertebrates). , 2002, Current opinion in genetics & development.

[6]  Yujing Sun,et al.  The loss of Trps1 suppresses ureteric bud branching because of the activation of TGF-β signaling. , 2013, Developmental biology.

[7]  N. Niikawa,et al.  Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. , 2001, American journal of human genetics.

[8]  Adam P. Rosebrock,et al.  A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. , 2013, Molecular cell.

[9]  A. Brinkmann,et al.  Structure and function of GC79/TRPS1, a novel androgen-repressible apoptosis gene , 2002, Apoptosis.

[10]  I. Hatamura,et al.  Trps1 deficiency enlarges the proliferative zone of growth plate cartilage by upregulation of Pthrp. , 2008, Bone.

[11]  D. Cimini,et al.  Histone hyperacetylation in mitosis prevents sister chromatid separation and produces chromosome segregation defects. , 2003, Molecular biology of the cell.

[12]  Daniel Birnbaum,et al.  Genome profiling of ERBB2-amplified breast cancers , 2010, BMC Cancer.

[13]  J. Blanchard.  Cyclin A2 transcriptional regulation: modulation of cell cycle control at the G1/S transition by peripheral cues. , 2000, Biochemical pharmacology.

[14]  J. Yates,et al.  Bora and the Kinase Aurora A Cooperatively Activate the Kinase Plk1 and Control Mitotic Entry , 2008, Science.

[15]  H. Northrup,et al.  A 4-megabase YAC contig that spans the Langer-Giedion syndrome region on human chromosome 8q24.1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1). , 1995, Genomics.

[16]  J. Yun,et al.  KPNA2 promotes cell proliferation and tumorigenicity in epithelial ovarian carcinoma through upregulation of c-Myc and downregulation of FOXO3a , 2013, Cell Death and Disease.

[17]  Shunji Itoh,et al.  Trps1 plays a pivotal role downstream of Gdf5 signaling in promoting chondrogenesis and apoptosis of ATDC5 cells , 2008, Genes to cells : devoted to molecular & cellular mechanisms.

[18]  R. Bronson,et al.  Deletion of the GATA Domain of TRPS1 Causes an Absence of Facial Hair and Provides New Insights into the Bone Disorder in Inherited Tricho-Rhino-Phalangeal Syndromes , 2002, Molecular and Cellular Biology.

[19]  Y. Bao,et al.  Low trichorhinophalangeal syndrome 1 gene transcript levels in basal-like breast cancer associate with mesenchymal-to-epithelial transition. , 2013, Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih.

[20]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[21]  Pier Paolo Di Fiore,et al.  The endocytic matrix , 2010, Nature.

[22]  R. Gambari,et al.  Correlation between Slug transcription factor and miR-221 in MDA-MB-231 breast cancer cells , 2012, BMC Cancer.

[23]  A. Fersht,et al.  Rescuing the function of mutant p53 , 2001, Nature Reviews Cancer.

[24]  G. Mills,et al.  Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer , 2012, Genome research.

[25]  W. Vainchenker,et al.  Constitutive expression of GATA-1 interferes with the cell-cycle regulation. , 1996, Blood.

[26]  T. Enver,et al.  GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21(WAF1) and p27(Kip1) proteins. , 2002, Blood.

[27]  S. Kong,et al.  GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium , 2008, Molecular and Cellular Biology.

[28]  M. Barbacid,et al.  Cell cycle, CDKs and cancer: a changing paradigm , 2009, Nature Reviews Cancer.

[29]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[30]  A. Christiano,et al.  Trps1 and Its Target Gene Sox9 Regulate Epithelial Proliferation in the Developing Hair Follicle and Are Associated with Hypertrichosis , 2012, PLoS genetics.

[31]  T. Tammela,et al.  Expression and copy number analysis of TRPS1, EIF3S3 and MYC genes in breast and prostate cancer , 2004, British Journal of Cancer.

[32]  C. Johannes,et al.  The multi zinc-finger protein Trps1 acts as a regulator of histone deacetylation during mitosis , 2013, Cell cycle.

[33]  H. Perlman,et al.  GATA-6 Induces p21Cip1 Expression and G1Cell Cycle Arrest* , 1998, The Journal of Biological Chemistry.

[34]  Ru-Fang Yeh,et al.  TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer , 2011, Science Signaling.

[35]  R. Shivdasani,et al.  Trps1, a regulator of chondrocyte proliferation and differentiation, interacts with the activator form of Gli3. , 2009, Developmental biology.

[36]  J. Murray,et al.  Expression and Relevance of TRPS-1: A New GATA Transcription Factor in Breast Cancer , 2011, Hormones & cancer.

[37]  M. Muenke,et al.  Genes and chromosomal breakpoints in the Langer-Giedion syndrome region on human chromosome 8 , 1999, Human Genetics.

[38]  S. Weger,et al.  SUMOylation modulates transcriptional repression by TRPS1 , 2007, Biological chemistry.

[39]  M. Salto‐Tellez,et al.  Manganese superoxide dismutase is a promising target for enhancing chemosensitivity of basal-like breast carcinoma. , 2014, Antioxidants & redox signaling.

[40]  G. Hortobagyi,et al.  Prognostic value of the trichorhinophalangeal syndrome-1 (TRPS-1), a GATA family transcription factor, in early-stage breast cancer. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[41]  D. Dornan,et al.  miR-221/222 Targets Adiponectin Receptor 1 to Promote the Epithelial-to-Mesenchymal Transition in Breast Cancer , 2013, PloS one.

[42]  G. Blobel,et al.  Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization. , 2007, Blood.

[43]  R. Derynck,et al.  Identification of the GATA Factor TRPS1 as a Repressor of the Osteocalcin Promoter* , 2009, The Journal of Biological Chemistry.

[44]  Yuan Qi,et al.  Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA , IDH 1 , EGFR , and NF 1 Citation Verhaak , 2010 .

[45]  Tariq Enver,et al.  High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. , 2009, Blood.

[46]  R. Spang,et al.  Role for E2F in Control of Both DNA Replication and Mitotic Functions as Revealed from DNA Microarray Analysis , 2001, Molecular and Cellular Biology.

[47]  B. Eussen,et al.  Characterization of a zinc-finger protein and its association with apoptosis in prostate cancer cells. , 2000, Journal of the National Cancer Institute.

[48]  Jun Hong,et al.  Increased Expression of TRPS1 Affects Tumor Progression and Correlates with Patients' Prognosis of Colon Cancer , 2013, BioMed research international.

[49]  A. Ooshima,et al.  Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling. , 2007, Developmental biology.

[50]  Yujing Sun,et al.  Aberrant expression of the P2 promoter-specific transcript Runx1 in epiphyseal cartilage of Trps1-null mice. , 2011, Experimental and molecular pathology.

[51]  G. Hortobagyi,et al.  Quantitative Immunohistochemical Analysis and Prognostic Significance of TRPS-1, a New GATA Transcription Factor Family Member, in Breast Cancer , 2010, Hormones & cancer.

[52]  L. Chodosh,et al.  GATA-1-Mediated Proliferation Arrest during Erythroid Maturation , 2003, Molecular and Cellular Biology.

[53]  L. Hartwell,et al.  Altered fidelity of mitotic chromosome transmission in cell cycle mutants of S. cerevisiae. , 1985, Genetics.

[54]  J Salvage,et al.  A matter of life and death. , 1981, Nursing times.

[55]  K. Ozato,et al.  The cyclin B1 gene is actively transcribed during mitosis in HeLa cells , 2001, EMBO reports.

[56]  S. Reed,et al.  The Cdk-associated protein Cks1 functions both in G1 and G2 in Saccharomyces cerevisiae. , 1993, Genes & development.

[57]  K. Herrup,et al.  Cdk5 Suppresses the Neuronal Cell Cycle by Disrupting the E2F1–DP1 Complex , 2010, The Journal of Neuroscience.

[58]  N. Niikawa,et al.  A 4 Mb cryptic deletion associated with inv(8)(q13.1q24.11) in a patient with trichorhinophalangeal syndrome type I. , 1997, Journal of medical genetics.

[59]  S. Gamble,et al.  Proteomic analysis of proteins regulated by TRPS1 transcription factor in DU145 prostate cancer cells. , 2007, Biochimica et biophysica acta.

[60]  A. Brinkmann,et al.  The atypical GATA protein TRPS1 represses androgen-induced prostate-specific antigen expression in LNCaP prostate cancer cells. , 2003, Biochemical and biophysical research communications.

[61]  Jason I. Herschkowitz,et al.  Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer , 2010, Breast Cancer Research.

[62]  Sirong He,et al.  MicroRNA-221 Mediates the Effects of PDGF-BB on Migration, Proliferation, and the Epithelial-Mesenchymal Transition in Pancreatic Cancer Cells , 2013, PloS one.

[63]  A. Christiano,et al.  Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis , 2012, Development.

[64]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[65]  H. Mitsuya,et al.  Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia. , 2007, Blood.

[66]  J. D. Engel,et al.  GATA-3 regulates hematopoietic stem cell maintenance and cell-cycle entry. , 2012, Blood.

[67]  E. Iversen,et al.  Charting the Landscape of Tandem BRCT Domain–Mediated Protein Interactions , 2012, Science Signaling.

[68]  J. Nevins,et al.  E2Fs link the control of G1/S and G2/M transcription , 2004, The EMBO journal.

[69]  E. Olson,et al.  The many roles of histone deacetylases in development and physiology: implications for disease and therapy , 2009, Nature Reviews Genetics.

[70]  T. Möröy,et al.  Nuclear interaction of the dynein light chain LC8a with the TRPS1 transcription factor suppresses the transcriptional repression activity of TRPS1. , 2003, Human molecular genetics.

[71]  Deon Venter,et al.  The gene associated with trichorhinophalangeal syndrome in humans is overexpressed in breast cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[72]  S. Reed,et al.  Cyclin-Dependent Kinase-Associated Proteins Cks1 and Cks2 Are Essential during Early Embryogenesis and for Cell Cycle Progression in Somatic Cells , 2008, Molecular and Cellular Biology.

[73]  R. Shivdasani,et al.  Transcriptional repression and developmental functions of the atypical vertebrate GATA protein TRPS1 , 2001, The EMBO journal.

[74]  H. Saya,et al.  Roles of aurora‐A kinase in mitotic entry and G2 checkpoint in mammalian cells , 2002, Genes to cells : devoted to molecular & cellular mechanisms.

[75]  J. Pines,et al.  Cyclins and the G2/M transition. , 1997, Cancer surveys.

[76]  S. Bates,et al.  Inhibitors of Histone Deacetylases Alter Kinetochore Assembly by Disrupting Pericentromeric Heterochromatin , 2005, Cell cycle.

[77]  I. Hatamura,et al.  Trps1 functions downstream of Bmp7 in kidney development. , 2009, Journal of the American Society of Nephrology : JASN.

[78]  G. Jenster,et al.  The TRPS1 transcription factor: androgenic regulation in prostate cancer and high expression in breast cancer. , 2004, Endocrine-related cancer.

[79]  S. Calvieri,et al.  Missense mutation in exon 7 of TRPS1 gene in an Italian family with a mild form of trichorhinophalangeal syndrome type I , 2007, The British journal of dermatology.

[80]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.