Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis
Philip D. Anderson, … , Isam-Eldin Eltoum, Sarki A. Abdulkadir
Philip D. Anderson, … , Isam-Eldin Eltoum, Sarki A. Abdulkadir
Published April 9, 2012
Citation Information: J Clin Invest. 2012;122(5):1907-1919. https://doi.org/10.1172/JCI58540.
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Research Article Oncology

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

Philip D. Anderson, Sydika A. McKissic, Monica Logan, Meejeon Roh, Omar E. Franco, Jie Wang, Irina Doubinskaia, Riet van der Meer, Simon W. Hayward, Christine M. Eischen, Isam-Eldin Eltoum, Sarki A. Abdulkadir

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Figure 4

Identification of a subset of direct Nkx3.1 target genes coregulated by Myc.

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Identification of a subset of direct Nkx3.1 target genes coregulated by ...
(A) Network analysis using GeneGO MetaCore software identifies a subset of direct Nkx3.1 target genes that are known to be bound by Myc (P = 3.94 × 10–169). Genes upregulated in the Nkx3.1 KO prostates are shown as blue circles, while those downregulated are indicated as red circles in the diagram. (B) Relative locations of actual Nkx3.1- and Myc-binding sites in selected Nkx3.1/Myc coregulated genes identified from genome-wide binding studies. (C) ChIP-PCR validation of Myc binding to selected shared Nkx3.1/Myc target genes in Myc-CaP mouse prostate adenocarcinoma cell line (top). These cells express Myc but not Nkx3.1, as shown in the inset Western blot. Results are representative of at least 2 independent experiments. (D) ChIP-qPCR validation of MYC and NKX3.1 binding to selected shared NKX3.1/MYC target genes in LNCaP human prostate adenocarcinoma cell line. These cells express both MYC and NKX3.1, as shown in the inset Western blot. Results are presented as mean ± sd from at least 2 independent experiments. See also Supplemental Tables 5 and 6.