Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-β cytostatic program and blocks the antiproliferative effect of TGF-β

Trinh, Bon Q.; Barengo, Nicolas; Naora, Honami

doi:10.1038/onc.2011.4

Cited by 33 publications

(55 citation statements)

References 49 publications

(101 reference statements)

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“…This induction occurs by two mechanisms. We identified that DLX4 prevents transforming growth factor-TGF--mediated repression of c-myc transcription, and also induces c-myc promoter activity independently of TGF-/Smad signaling (Trinh et al, 2011). DLX5, another member of the DLX family, has also been found to directly activate c-myc transcription in lung cancer cells (Xu and Testa, 2009).…”

Section: Sustained Proliferative Signalingmentioning

confidence: 94%

“…We have found that overexpression of DLX4 in ovarian cancer cells induces FGF-2 expression, increases clonogenicity in vitro and promotes tumor growth in vivo (Hara et al, 2007), but it is not known whether DLX4 directly activates FGF-2 transcription. We recently found that DLX4 also induces expression of c-Myc (Trinh et al, 2011). This induction occurs by two mechanisms.…”

Section: Sustained Proliferative Signalingmentioning

confidence: 99%

“…TGF- receptor mutations have been detected in 12 to 31% of ovarian cancers, but many TGF--resistant ovarian cancers have been found to express functional receptors and rarely have Smad4 mutations (Yamada et al, 1999;Wang et al, 2000;FrancisThickpenny et al, 2001). We have found that DLX4 blocks the anti-proliferative effect of TGF- by inactivating transcriptional control of the TGF- cytostatic program through three distinct but integrated mechanisms (Trinh et al, 2011). Firstly, DLX4 directly binds Smad4 and prevents Smad4 from forming transcriptional complexes with Smad2 and Smad3.…”

Section: Evasion Of Growth-suppressorsmentioning

confidence: 99%

“…Because homeoproteins of a given family share regions of extensive homology, it is not surprising that family members have overlapping functions. For example, both DLX4 and DLX5 induce c-Myc expression (Xu and Testa 2009;Trinh et al, 2011). On the other hand, MSX1 induces expression of growth arrest genes such as GADD153 and inhibits proliferation of ovarian cancer cells (Park et al, 2001), whereas MSX2 promotes ovarian cancer growth (Zhai et al, 2011).…”

Section: Sustained Proliferative Signalingmentioning

confidence: 99%

See 3 more Smart Citations

Homeobox Genes and Their Functional Significance in Ovarian Tumorigenesis

Trinh¹,

Naora²

2012

Ovarian Cancer - Basic Science Perspective

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Section: Sustained Proliferative Signalingmentioning

confidence: 94%

Section: Sustained Proliferative Signalingmentioning

confidence: 99%

Section: Evasion Of Growth-suppressorsmentioning

confidence: 99%

Section: Sustained Proliferative Signalingmentioning

confidence: 99%

See 2 more Smart Citations

Homeobox Genes and Their Functional Significance in Ovarian Tumorigenesis

Trinh¹,

Naora²

2012

Ovarian Cancer - Basic Science Perspective

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“…Moreover, BP1 inhibits TGF-β-mediated induction of p15 Ink4B and p21 WAF1/Cip1 expression by blocking the TGF-β/Smad signaling pathway in normal and malignant epithelial cell lines [53].…”

Section: Brca1mentioning

confidence: 99%

BP1, a Potential Biomarker for Breast Cancer Prognosis

et al. 2018

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Homeobox genes are critical in tumor development. An isoform protein of DLX4 called BP1 is expressed in 80% of invasive ductal breast carcinomas. BP1 overexpression is implicated in an aggressive phenotype and poor prognosis. BP1 upregulation is associated with estrogen receptor negativity so those tumors do not respond to antiestrogens. Breast cancer is the second leading cause of death in women. BP1 could serve as both a novel prognostic biomarker for breast cancer and a therapeutic target. In this review, we address the role of BP1 protein in tumorigenesis of breast cancer and four other malignancies. A number of functions of BP1 in cancer are also discussed. Female breast cancer represents 14.6% of all new cancer cases in the USA according to the National Cancer Institute [1]. An estimated 252,710 new cases of invasive breast cancer are expected to be diagnosed in women in the USA in 2017. It is also estimated that 30% of newly diagnosed cancers in women will be breast cancers [2].Breast cancer is a hormone-dependent cancer, and estrogen (17β-estradiol) plays a critical role in the initiation and the progression of this disease [3]. Estrogen, produced by the ovaries, affects the growth and function of mammary glands by binding to the estrogen receptors (ERs) α and β. Through dimerization of the receptor, translocation to the nucleus and interaction with estrogen response elements in the promoter region of targeted genes, gene expression leads to multiple biological outcomes [4]. 70% of invasive breast cancers are ER positive (ER + ), making antiestrogens essential in treating these patients [5]. Targeting the ER or its pathway using tamoxifen (a selective ER modulator) or fulvestrant (an ER downregulator) have been successful therapeutic strategies [6]. However, drug resistance remains a major challenge in treating breast cancer. The main pathway leading to resistance involves loss of ER expression or selection of an ER-negative population of cells. Moreover, these ER-negative breast cancers have a higher histologic grade and a higher proliferative rate and are associated with poorer prognosis. This highlights the key importance of finding alternative targets to treat these patients and identifying a new biomarker for breast cancer prognosis.BP1 protein, an isoform of DLX4, belongs to the homeobox gene family which includes regulatory genes implicated in early development and cell differentiation that are frequently dysregulated in cancer [7]. Therefore, targeting BP1 may provide a new avenue for breast cancer management. The first related paper was published in 1998, when the authors mapped this new homeobox gene to chromosome 17q21 and characterized its role in repression of the β-globin gene [8]. During the last 20 years, several studies have been carried out to measure BP1 levels in breast cancer and other carcinomas, with the primary aim of confirming its diagnostic and prognostic value as a biomarker. We are writing this review to consolidate and update all of the available information on BP1. Homeobox...

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DLX4 hypermethylation is a prognostically adverse indicator in de novo acute myeloid leukemia

et al. 2016

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Hypermethylation of distal-less homeobox 4 (DLX4) has been increasingly identified in several cancers. Our study was aimed to determine the role of DLX4 methylation in regulating DLX4 expression and further analyze its clinical significance in de novo acute myeloid leukemia (AML) patients. DLX4 methylation level was detected by real-time quantitative methylation-specific PCR and bisulfite sequencing PCR. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC) was used for demethylation studies. Clinical significance of DLX4 methylation was obtained by the comparison between the patients with and without DLX4 methylation. DLX4 was significantly methylated in AML patients compared with controls (P < 0.001). DLX4 methylation was negatively associated with DLX7 (the shorter DLX4 isoform) (R = -0.202, P = 0.021) but not BP1 (the longer DLX4 isoform) (R = -0.049, P = 0.582) expression in AML patients. DLX7 and BP1 messenger RNA (mRNA) were significantly increased after 5-aza-dC treatment in leukemic cell lines THP1 and Kasumi-1. DLX4 methylated patients showed significantly higher frequency of U2AF1 mutation compared with DLX4 unmethylated patients (P = 0.043). Both all AML and non-M3 patients with DLX4 methylation presented significantly lower complete remission rate than those with DLX4 unmethylation (P = 0.001 and <0.001, respectively). DLX4 methylated cases had significantly shorter overall survival than DLX4 unmethylated cases among both all AML (P = 0.003), non-M3 AML (P = 0.001), and cytogenetically normal AML (P = 0.032). Multivariate analysis confirmed that DLX4 methylation was independent risk factor in both all AML and non-M3 patients. Our study indicates that DLX4 hypermethylation is negatively associated with DLX7 expression and predicts poor clinical outcome in de novo AML patients.

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Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-β cytostatic program and blocks the antiproliferative effect of TGF-β

Cited by 33 publications

References 49 publications

Homeobox Genes and Their Functional Significance in Ovarian Tumorigenesis

Homeobox Genes and Their Functional Significance in Ovarian Tumorigenesis

BP1, a Potential Biomarker for Breast Cancer Prognosis

DLX4 hypermethylation is a prognostically adverse indicator in de novo acute myeloid leukemia

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