Germ-Line Mutation of <i>NKX3.1</i> Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function

Zheng, S. Lilly; Ju, Jeong Ho; Chang, Bao Li; Ortner, Elizabeth; Sun, Jielin; Isaacs, Sarah D.; Sun, Jishang; Wiley, Kathy E.; Liu, Wennuan; Zemedkun, Micheas; Walsh, Patrick C.; Ferretti, James A.; Gruschus, James M.; Isaacs, William B.; Gelmann, Edward P.; Xu, Jianfeng

doi:10.1158/0008-5472.can-05-1550

Cited by 47 publications

(43 citation statements)

References 47 publications

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“…The prevalence of Hox gene hypermethylation in TRAMP suggests that Hox family genes may function as tumor suppressors in prostate cancer. Consistent with this idea, the Hox gene Nkx3.1 is an established prostate tumor suppressor in mice and humans (47,48). Interestingly, Nkx3.1 is also epigenetically inactivated in prostate cancer, although this seems to primarily occur at the level of protein expression (47).…”

Section: Discussionmentioning

confidence: 78%

DNA Methylation Pathway Alterations in an Autochthonous Murine Model of Prostate Cancer

et al. 2006

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We examined the DNA methylation pathway in an autochthonous murine prostate cancer model, transgenic adenocarcinoma of mouse prostate (TRAMP). We observed that, compared with strain-matched normal prostates, primary and metastatic TRAMP tumors display increased cytosine DNA methyltransferase (Dnmt) activity, Dnmt1 and Dnmt3b protein expression, and Dnmt1, Dnmt3a, and Dnmt3b mRNA expression. Increased expression of Dnmt genes correlates with increased expression of cyclin A and E2F target genes, implicating increased cell proliferation and Rb inactivation in Dnmt overexpression. We analyzed DNA methylation in TRAMP and found that global levels of 5-methyl-2 ¶-deoxycytidine are unaltered, whereas specific tumors display centromeric repeat hypomethylation. To interrogate locus-specific methylation, we did restriction landmark genomic scanning (RLGS) on normal prostates and primary tumors. In primary tumors, 2.3% of f1,200 analyzed loci display aberrant DNA hypermethylation, whereas a considerably smaller number of events show hypomethylation. The pattern of RLGS changes was nonrandom, indicating a coordinated methylation defect. Two specific genes identified by RLGS were studied in detail. Surprisingly, methylation of a downstream exon of p16(INK4a) (p16) was the highest frequency hypermethylation event identified in TRAMP, where it is associated with increased p16 mRNA and protein expression. In contrast, hypermethylation of the 5 ¶ CpG island region of the homeobox gene Irx3 in TRAMP is associated with reduced gene expression. In summary, our data reveal a systemic DNA methylation pathway defect in TRAMP reminiscent of human prostate cancer, supporting the use of this model to investigate the functional role of DNA methylation pathway alterations in prostate cancer development. (Cancer Res 2006; 66(24): 11659-67)

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Section: Discussionmentioning

confidence: 78%

DNA Methylation Pathway Alterations in an Autochthonous Murine Model of Prostate Cancer

et al. 2006

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“…A far greater number of genes are located at the 8p21.3 consensus region, with at least 37 known protein-coding genes. Some of these genes, including NKX3.1, have been previously associated with HPC (15).…”

Section: Resultsmentioning

confidence: 99%

Integration of Somatic Deletion Analysis of Prostate Cancers and Germline Linkage Analysis of Prostate Cancer Families Reveals Two Small Consensus Regions for Prostate Cancer Genes at 8p

et al. 2007

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The evidence for tumor suppressor genes at 8p is well supported by many somatic deletion studies and genetic linkage studies. However, it remains a challenge to pinpoint the tumor suppressor genes at 8p primarily because the implicated regions are broad. In this study, we attempted to narrow down the implicated regions by incorporating evidence from both somatic and germline studies. Using high-resolution Affymetrix arrays, we identified two small common deleted regions among 55 prostate tumors at 8p23.1 (9.8-11.5 Mb) and 8p21.3 (20.6-23.7 Mb). Interestingly, our fine mapping linkage analysis at 8p among 206 hereditary prostate cancer families also provided evidence for linkage at these two regions at 8p23.1 (5.8-11.2 Mb) and at 8p21.3 (19.6-23.9 Mb). More importantly, by combining the results from the somatic deletion analysis and genetic linkage analysis, we were able to further narrow the regions to f1.4 Mb at 8p23.1 and f3.1 Mb at 8p21.3. These smaller consensus regions may facilitate a more effective search for prostate cancer genes at 8p. [Cancer Res 2007;67(9):4098-103]

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“…Recent studies indicate that Nkx3.1 marks a population of castration-resistant luminal stem cells and is required for stem cell self renewal (6). Nkx3.1 protein is commonly attenuated in mouse and human prostate tumors (7,8), and a germ line sequence variant that impairs NKX3.1 DNA binding has been associated with hereditary prostate cancer (9). More recently, Genome-Wide Association Studies (GWAS) identified a functional variant in NKX3.1 associated with reduced gene expression as a risk factor for sporadic prostate cancer (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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

Anderson

McKissic²,

Logan

et al. 2012

J. Clin. Invest.

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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.

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Germ-Line Mutation of NKX3.1 Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function

Cited by 47 publications

References 47 publications

DNA Methylation Pathway Alterations in an Autochthonous Murine Model of Prostate Cancer

DNA Methylation Pathway Alterations in an Autochthonous Murine Model of Prostate Cancer

Integration of Somatic Deletion Analysis of Prostate Cancers and Germline Linkage Analysis of Prostate Cancer Families Reveals Two Small Consensus Regions for Prostate Cancer Genes at 8p

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

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