Homeobox gene expression in cancer: Insights from developmental regulation and deregulation

Samuel, Shaija; Naora, Honami

doi:10.1016/j.ejca.2005.08.014

Cited by 174 publications

(172 citation statements)

References 103 publications

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“…Many homeobox genes are aberrantly expressed in a variety of hematological malignancies and solid tumors, most commonly showing up-regulation and less commonly down-regulation (24,25). However, many of these genes are not expressed in adult tissues, including the lung (24,26).…”

Section: Discussionmentioning

confidence: 99%

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Rauch¹,

Wang²,

Zhang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

260

221

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De novo methylation of CpG islands is a common phenomenon in human cancer, but the mechanisms of cancer-associated DNA methylation are not known. We have used tiling arrays in combination with the methylated CpG island recovery assay to investigate methylation of CpG islands genome-wide and at high resolution. We find that all four HOX gene clusters on chromosomes 2, 7, 12, and 17 are preferential targets for DNA methylation in cancer cell lines and in early-stage lung cancer. CpG islands associated with many other homeobox genes, such as SIX, LHX, PAX, DLX, and Engrailed, were highly methylated as well. Altogether, more than half (104 of 192) of all CpG island-associated homeobox genes in the lung cancer cell line A549 were methylated. Analysis of paralogous HOX genes showed that not all paralogues undergo cancerassociated methylation simultaneously. The HOXA cluster was analyzed in greater detail. Comparison with ENCODE-derived data shows that lack of methylation at CpG-rich sequences correlates with presence of the active chromatin mark, histone H3 lysine-4 methylation in the HOXA region. Methylation analysis of HOXA genes in primary squamous cell carcinomas of the lung led to the identification of the HOXA7-and HOXA9-associated CpG islands as frequent methylation targets in stage 1 tumors. Homeobox genes are potentially useful as DNA methylation markers for early diagnosis of the disease. The finding of widespread methylation of homeobox genes lends support to the hypothesis that a substantial fraction of genes methylated in human cancer are targets of the Polycomb complex.DNA methylation ͉ HOX genes ͉ chromatin ͉ Polycomb

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Section: Discussionmentioning

confidence: 99%

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Rauch¹,

Wang²,

Zhang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

260

221

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“…22,23 In humans, there are over 200 such genes containing this motif, and many of them have been identified as aberrantly expressed in cancers. 24,25 For example, overexpression of HOXC6, PAX2, and BP1 have been described in PCa. [26][27][28] We have previously shown that methylation of homeobox genes is a common event in PCa, 14 whereas others have shown similar results in so-called methylation 'hot spots' within HOX loci.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of HOXD3 as a marker of prostate cancer progression

Kron

Liu

Pethe

et al. 2010

Laboratory Investigation

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DNA methylation in gene promoters causes gene silencing and is a common event in cancer development and progression. The ability of aberrant methylation events to serve as diagnostic and prognostic markers is being appreciated for many cancers, including prostate cancer. Using quantitative MethyLight technology, we evaluated the relationship between HOXD3 methylation and clinicopathological parameters including biochemical recurrence, pathological stage, Gleason score (GS), and Gleason pattern in a series of 232 radical prostatectomies performed between 1998 and 2001. HOXD3 methylation was significantly greater in GS 7 cancers vs GSr6 cancers (P-value o0.001) as well as pT3/pT4 vs pT2 cancers (P-value o0.001). The proportion of cases with high methylation in GS 7 vs rGS 6 and pT3/pT4 vs pT2 were also significantly different (P-values ¼ 0.002 and 0.005, respectively). There were also significant increases in methylation from Gleason pattern 2-3 and from pattern 3 to 4/5 (paired t-test P-values ¼ 0.01 and o0.001, respectively), whereas methylation from lymph node metastases was decreased when compared with matched tumor tissue (P-value ¼ 0.029). HOXD3 methylation was associated with biochemical recurrence in univariate analysis (P-value ¼ 0.043) and showed evidence for interaction with pathological stage as a predictor variable in Cox regression analysis (P-value ¼ 0.028). The results indicate that HOXD3 methylation distinguishes low-grade prostate cancers from intermediate and high-grade ones and may also have prognostic value when considered together with pathological stage.

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“…It is widely accepted that tumorigenesis is an aberrant form of organogenesis and that both normal developmental and neoplastic processes progress through common pathways (1). This is illustrated by the large number of developmentally regulated genes and signal transduction pathways with demonstrated roles in neoplastic progression.…”

Section: Introductionmentioning

confidence: 99%

PAX5α Enhances the Epithelial Behavior of Human Mammary Carcinoma Cells

Vidal

Perry

Vouyovitch

et al. 2010

Molecular Cancer Research

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Deregulated PAX5 expression has been associated with metastatic mammary carcinoma, although the precise role of PAX5 in cancer progression is unclear. Stable forced expression of PAX5α in the mammary carcinoma cell lines MCF-7 and MDA-MB-231 reduced cell cycle progression, cell survival, and anchorage-independent cell growth. In xenograft studies, forced expression of PAX5α was associated with a significant reduction in tumor volume. Furthermore, forced expression of PAX5α in mammary carcinoma cells resulted in altered cell morphology with resultant enhancement of epithelial cell characteristics. Morphologic changes were associated with localization of β-CATENIN at cell-cell junctions and with altered mRNA expression of mesenchymal markers in mammary carcinoma cells. In addition, forced expression of PAX5α in MCF-7 and MDA-MB-231 cells significantly reduced cell migration and invasion. Concomitantly, small interfering RNA-mediated depletion of PAX5α increased MCF-7 total cell number, cell motility, migration, and invasion. These studies show that PAX5α enhances the epithelial characteristics of mammary carcinoma cells, reminiscent of mesenchymal to epithelial transition. Mol Cancer Res; 8(3); 444-56. ©2010 AACR.

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Homeobox gene expression in cancer: Insights from developmental regulation and deregulation

Cited by 174 publications

References 103 publications

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

DNA methylation of HOXD3 as a marker of prostate cancer progression

PAX5α Enhances the Epithelial Behavior of Human Mammary Carcinoma Cells

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