title: Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis.
abstract: Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Anderson
authors.forename: Sydika A
authors.initials: SA
authors.lastname: McKissic
authors.forename: Monica
authors.initials: M
authors.lastname: Logan
authors.forename: Meejeon
authors.initials: M
authors.lastname: Roh
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Irina
authors.initials: I
authors.lastname: Doubinskaia
authors.forename: Riet
authors.initials: R
authors.lastname: van der Meer
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
authors.forename: Isam-Eldin
authors.initials: IE
authors.lastname: Eltoum
authors.forename: Sarki A
authors.initials: SA
authors.lastname: Abdulkadir
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016384:Consensus Sequence; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; C489427:MYC protein, human; C491178:NKX3-1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors