Epigenetic silencing of HOPX contributes to cancer aggressiveness in breast cancer

Kikuchi, Masatoshi; Katoh, Hiroshi; Waraya, Mina; Tanaka, Yôko; Ishii, Satoru; Tanaka, Toshimichi; Nishizawa, Nobuyuki; Yokoi, Keigo; Minatani, Naoko; Ema, Akira; Kosaka, Yoshimasa; Tanino, Hirokazu; Yamashita, Keishi; Watanabe, Masahiko

doi:10.1016/j.canlet.2016.10.017

Cited by 26 publications

(36 citation statements)

References 29 publications

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“…De-differentiation is recognized as the morphological loss of lineage identity, and it is associated with high tumor heterogeneity and poor prognosis in different cancer types [39,40]. However, how cell de-differentiation is linked to both tumorigenesis and cancer development is still unclear and undoubtedly represents an emerging field of study [41][42][43].…”

Section: Epigenetic Reprogramming: the Common Switch Through Tumor Dementioning

confidence: 99%

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Citron

Fabris

2020

Cancers

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Extensive efforts recently witnessed the complexity of cancer biology; however, molecular medicine still lacks the ability to elucidate hidden mechanisms for the maintenance of specific subclasses of rare tumors characterized by the silent onset and a poor prognosis (e.g., ovarian cancer, pancreatic cancer, and glioblastoma). Recent mutational fingerprints of human cancers highlighted genomic alteration occurring on epigenetic modulators. In this scenario, the epigenome dependency of cancer orchestrates a broad range of cellular processes critical for tumorigenesis and tumor progression, possibly mediating escaping mechanisms leading to drug resistance. Indeed, in this review, we discuss the pivotal role of chromatin remodeling in shaping the tumor architecture and modulating tumor fitness in a microenvironment-dependent context. We will also present recent advances in the epigenome targeting, posing a particular emphasis on how this knowledge could be translated into a feasible therapeutic approach to individualize clinical settings and improve patient outcomes.

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Section: Epigenetic Reprogramming: the Common Switch Through Tumor Dementioning

confidence: 99%

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Citron

Fabris

2020

Cancers

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“…We previously developed pharmacological reversal of epigenetic silencing (3) and uncovered a myriad of transcriptionally repressed genes, such as PGP9.5 (4), NMDAR2B (5), DFNA5 (6), and HOPX (7) in human gastrointestinal cancers. Until now, we have originally reported cysteine dioxygenase type 1 (CDO1) and homeobox only protein (HOP) homeobox (HOPX) as novel methylation genes in primary BC (8,9). Through clinicopathological analysis including prognostic information, we have already reported a positive relationship of both genes to prognosis of BC (9,10).…”

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confidence: 99%

“…Until now, we have originally reported cysteine dioxygenase type 1 (CDO1) and homeobox only protein (HOP) homeobox (HOPX) as novel methylation genes in primary BC (8,9). Through clinicopathological analysis including prognostic information, we have already reported a positive relationship of both genes to prognosis of BC (9,10).…”

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confidence: 99%

“…On the other hand, reports on aberrant promoter DNA methylation and their relations to BC prognosis are reported in about 700 papers until 2018, which have covered more than 200 genes, while only 31 genes described by the 48 papers were investigated by quantitative methylation specific PCR (Q-MSP). Then, among the 48 papers, only three genes, CDO1 (10,13), PITX2 (14,15), and HOPX (9) were proven to be independent prognostic factors by multivariate prognostic analysis. There have been no reports describing all three genes simultaniously.…”

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confidence: 99%

“…From our laboratory, promoter DNA methylation for CDO1 and HOPX was assessed for highly relevant prognostic factors in primary BC, and their prognostic relevance were seen, especially for CDO1 hypermethylation in triple-negative type (10) and HOPX hypermethylation in HER2-negative type (9). In Q-MSP, prognostic value is assessed by the most optimized cut-off values instead of presence or absence of methylation.…”

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Differential Prognostic Relevance of Promoter DNA Methylation of CDO1 and HOPX in Primary Breast Cancer

et al. 2019

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Background/Aim: We previously identified that promoter DNA methylation of cysteine dioxygenase type 1 (CDO1) and homeobox only protein homeobox (HOPX) were both cancer specific, and have a clinical potential as prognostic biomarkers in breast cancer (BC). The present study compared the differential prognostic relevance of methylation status of the CDO1 and HOPX genes in BC. Materials and Methods: Methylation levels (TaqMethVs) were quantified in 7 BC cell lines and 133 BC patients by TaqMan methylation-specific PCR and functional traits were explored for CDO1. Results: TaqMethVs were associated between CDO1 and HOPX (r 2 =0.072, p=0.002). Multivariate Cox proportional hazards model could identify CDO1 hypermethylation as well as Ki-67 as independent prognostic factors related to disease-specific survival (p=0.016, p<0.001). Overexpression of CDO1 decreased the anchorage-independent growth capacity in BC cell lines. Conclusion: CDO1 is a definite tumor suppressor gene, while its prognostic relevance was more than expected in the context of its functional relevance. Breast cancer (BC) is the most common cancer in women worldwide. Recent estimates by the International Agency for Research on Cancer (IARC) show that BC is the most commonly diagnosed cancer in women, making up 24.2% or about 1 in 4 of all new cancer cases diagnosed in women worldwide (1). The incidence of BC is increasing in the 2289

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Restoration of GATA4 expression impedes breast cancer progression by transcriptional repression of ReLA and inhibition of NF‐κB signaling

Han

Tang

Chen

et al. 2018

J of Cellular Biochemistry

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There are increasing reports of aberrant expression of GATA4, correlated with oncogenesis and malignant progression in some solid tumors, but whether GATA4 functions as an oncogenic driver or a tumor suppressor in carcinogenesis remains controversial. Because the role and mechanism of GATA4 in breast cancer (BrCa) remain poorly understood, we focused on the expression of GATA4 in BrCa cell lines and tissues and its mechanism in breast oncogenesis. Semiquantitative real-time polymerase chain reaction (RT-PCR), quantitative RT-PCR, Western blot analysis, and immunohistochemistry were used to detect expression of GATA4 in BrCa cell lines and adjacent breast tissues. Methylation statuses of the GATA4 promoter were studied using methylation-specific PCR in BrCa cell lines.The effects of GATA4 on proliferation, invasion, and cell cycle were also analyzed. Compared with adjacent breast tissue, GATA4 expression in BrCa tissue and cell lines was obviously lower and low expression levels of GATA4 predicted poor outcome. Methylation of GATA4 occurred in almost all of BrCa cell lines . GATA4 overexpression decreased viability, invasion, migration, and epithelial-to-mesenchymal transition of MB-231 and BT549 cells, and markedly induced cell cycle arrest and apoptosis. Exogenous expression GATA4 accompanied a significant alteration of MMP2, MMP3, E-cadherin, and N-cadherin expression and induction of the caspase-8 pathway. Moreover, GATA4 could directly repress RelA (p65) transcription, reduce the nuclear phosphorylation-p65 and upregulate inhibitor kappa B expression. Altogether, GATA4 plays a tumor-suppressive role via repression of NF-κB signaling in BrCa cells. Our findings suggest that GATA4 is a potential prognostic biomarker and gene therapeutic target for human BrCa.

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Epigenetic silencing of HOPX contributes to cancer aggressiveness in breast cancer

Cited by 26 publications

References 29 publications

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Differential Prognostic Relevance of Promoter DNA Methylation of CDO1 and HOPX in Primary Breast Cancer

Restoration of GATA4 expression impedes breast cancer progression by transcriptional repression of ReLA and inhibition of NF‐κB signaling

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