Homeobox Gene Deregulation: Impact on the Hallmarks of Cancer

Haria, Dhwani; Naora, Honami

doi:10.1166/ch.2013.1007

Cited by 43 publications

(35 citation statements)

References 89 publications

(123 reference statements)

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“…A previous report demonstrated that 23 out of 39 HOX cluster genes are expressed in human adrenal glands and that HoxB2, B4, B5, and B9 are expressed in order from the capsule to the inner zona reticularis in the rat adrenal cortex (29). Because some HOX genes are involved in cellular differentiation and tumorigenesis (45), it is interesting to speculate that aberrant HOX gene activation contributes to tumorigenesis in APA.…”

Section: Discussionmentioning

confidence: 99%

Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

Murakami

Yoshimoto

Nakabayashi

et al. 2015

European Journal of Endocrinology

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Objective: The pathophysiology of aldosterone-producing adenomas (APA) has been investigated intensively through genetic and genomic approaches. However, the role of epigenetics in APA is not fully understood. In the present study, we explored the relationship between gene expression and DNA methylation status in APA. Methods: We conducted an integrated analysis of transcriptome and methylome data of paired APA-adjacent adrenal gland (AAG) samples from the same patient. The adrenal specimens were obtained from seven Japanese patients with APA who underwent adrenalectomy. Gene expression and genome-wide CpG methylation profiles were obtained from RNA and DNA samples that were extracted from those seven paired tissues. Results: Methylome analysis showed global CpG hypomethylation in APA relative to AAG. The integration of gene expression and methylation status showed that 34 genes were up-regulated with CpG hypomethylation in APA. Of these, three genes (CYP11B2, MC2R, and HPX) may be related to aldosterone production, and five genes (PRRX1, RAB38, FAP, GCNT2, and ASB4) are potentially involved in tumorigenesis. Conclusion: The present study is the first methylome analysis to compare APA with AAG in the same patients. Our integrated analysis of transcriptome and methylome revealed DNA hypomethylation in APA and identified several up-regulated genes with DNA hypomethylation that may be involved in aldosterone production and tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

Murakami

Yoshimoto

Nakabayashi

et al. 2015

European Journal of Endocrinology

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“…Thus, these diverse DNA-binding proteins have the potential to alter DNA damage signaling in tissue-specific ways correlating with their developmental programs. The effects of homeodomain proteins may also have important consequences in cancer since upregulation or misexpression of these transcription factors is observed in some tumor types ( Haria and Naora, 2013 ). Further work is clearly necessary to decipher the relationship between these factors and ATM activation in these different biological settings.…”

Section: Discussionmentioning

confidence: 99%

Homeodomain Proteins Directly Regulate ATM Kinase Activity

Johnson¹,

Lee²,

Myler³

et al. 2018

Cell Reports

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SUMMARYAtaxia-telangiectasia mutated (ATM) is a serine/threonine kinase that coordinates the response to DNA double-strand breaks and oxidative stress. NKX3.1, a prostate-specific transcription factor, was recently shown to directly stimulate ATM kinase activity through its highly conserved homeodomain. Here, we show that other members of the homeodomain family can also regulate ATM kinase activity. We found that six representative homeodomain proteins (NKX3.1, NKX2.2, TTF1, NKX2.5, HOXB7, and CDX2) physically and functionally interact with ATM and with the Mre11-Rad50-Nbs1 (MRN) complex that activates ATM in combination with DNA double-strand breaks. The binding between homeodomain proteins and ATM stimulates oxidation-induced ATM activation In Vitro but inhibits ATM kinase activity in the presence of MRN and DNA and in human cells. These findings suggest that many tissue-specific homeodomain proteins may regulate ATM activity during development and differentiation and that this is a unique mechanism for the control of the DNA damage response.

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“…These included several homeobox genes (HOX), forkhead box (FOX) families, G protein-coupled receptors (GPR), and zinc finger proteins (ZNF) (Supplementary Table S3). HOX genes belong to a large family that encodes for proteins functioning as critical master regulatory transcription factors during embryogenesis; where some of them reported overexpressed while others downregulated in cancer8283. The roles of HOX genes methylation and downregulation in the biology of EAC or as biomarkers for cancer risk need to be determined.…”

Section: Resultsmentioning

confidence: 99%

Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas

Peng

Guo

Chen

et al. 2017

Sci Rep

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The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. In this study, we carried out an integrative molecular analysis to identify interactions between genomic and epigenomic alterations in regulating gene expression networks in EAC. We detected significant alterations in DNA copy numbers (CN), gene expression levels, and DNA methylation profiles. The integrative analysis demonstrated that altered expression of 1,755 genes was associated with changes in CN or methylation. We found that expression alterations in 84 genes were associated with changes in both CN and methylation. These data suggest a strong interaction between genetic and epigenetic events to modulate gene expression in EAC. Of note, bioinformatics analysis detected a prominent K-RAS signature and predicted activation of several important transcription factor networks, including β-catenin, MYB, TWIST1, SOX7, GATA3 and GATA6. Notably, we detected hypomethylation and overexpression of several pro-inflammatory genes such as COX2, IL8 and IL23R, suggesting an important role of epigenetic regulation of these genes in the inflammatory cascade associated with EAC. In summary, this integrative analysis demonstrates a complex interaction between genetic and epigenetic mechanisms providing several novel insights for our understanding of molecular events in EAC.

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Homeobox Gene Deregulation: Impact on the Hallmarks of Cancer

Cited by 43 publications

References 89 publications

Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

Homeodomain Proteins Directly Regulate ATM Kinase Activity

Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas

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