Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis.

Anderson PD, McKissic SA, Logan M, Roh M, Franco OE, Wang J, Doubinskaia I, van der Meer R, Hayward SW, Eischen CM, Eltoum IE, Abdulkadir SA
J Clin Invest. 2012 122 (5): 1907-19

PMID: 22484818 · PMCID: PMC3336973 · DOI:10.1172/JCI58540

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.

MeSH Terms (24)

Animals Base Sequence Binding Sites Cell Line Cell Transformation, Neoplastic Consensus Sequence Gene Expression Regulation, Neoplastic Gene Regulatory Networks Homeodomain Proteins Humans Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, SCID Mice, Transgenic Neoplasm Transplantation Prostatic Intraepithelial Neoplasia Prostatic Neoplasms Proto-Oncogene Proteins c-myc Rats Sequence Analysis, DNA Transcription, Genetic Transcription Factors

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