Characterization of the Nasopharyngeal Carcinoma Methylome Identifies Aberrant Disruption of Key Signaling Pathways and Methylated Tumor Suppressor Genes

Li, Li Li; Zhang, Yuan; Fan, Yichao; Sun, Kun; Su, Xianwei; Du, Zhenfang; Tsao, Sai Wah; Loh, Thomas; Sun, Hao; Chan, Anthony T.C.; Zeng, Yi Xin; Chan, Wai Yee; Chan, Francis K.L.; Tao, Qian

doi:10.2217/epi.14.79

Cited by 51 publications

(49 citation statements)

References 86 publications

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“…First, we examined the effects of SFRP1 on NPC cells using MTT, colony formation, wound-healing, and Transwell assays, which showed that cell proliferation, invasion, and migration abilities were significantly suppressed in cells overexpressing SFRP1. The role of SFRP1 in NPC proliferation in vitro was consistent with Li and colleagues (19). Nude mice xenografts tumor model and lung colonization model were used to investigate the effects of SFRP1 in vivo and revealed that SFRP1 overexpression inhibited tumor aggressiveness of NPC.…”

Section: Discussionsupporting

confidence: 75%

“…However, emerging evidence has indicated that SFRP1 may also be highly expressed in carcinomas and promote tumor proliferation or migration, such as in basal-like breast cancer (42), gastric cancer (43), and metastatic renal carcinoma (44). Recently, it has been reported that SFRP1 could suppress NPC cell proliferation in vitro (19). Notably, there is no research on SFRP1 in NPC metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…More importantly, SFRP1 has been reported to be associated with cancer therapy. Recently, it has been reported that SFRP1 could suppress NPC cells proliferation in vitro (19). However, it remains unclear whether SFRP1 plays a direct role in NPC metastasis.…”

Section: Introductionmentioning

confidence: 99%

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Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Ren

Zhou

Jiang

et al. 2015

Cancer Prevention Research

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Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/b-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36-3.94; P ¼ 0.002], diseasefree survival (HR, 1.98; 95% CI, 1.23-3.18; P ¼ 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19-3.59; P ¼ 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. b-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/b-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Ren

Zhou

Jiang

et al. 2015

Cancer Prevention Research

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“…In addition to deletion, epigenetic modifications of DACT genes were also reported. For instance, DACT1 and DACT2 were reported to be methylated in hepatocellular carcinoma, oral squamous, gastric cancer, nasopharyngeal carcinoma, thyroid cancer, colon cancer and lung cancer (10,(26)(27)(28)(29)(30)(31). In addition, DACT3 was identified to have histone modifications in colorectal cancer (25,26,32).…”

Section: Discussionmentioning

confidence: 99%

Methylation of DACT2 contributes to the progression of breast cancer through activating WNT signaling pathway

Wang

Yang

et al. 2017

Oncol Lett

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Abstract. The activation of the Wnt/β-catenin signaling pathway has been demonstrated to play important roles in breast carcinogenesis and to be associated with a poorer prognosis in breast cancer patients. However, genetic mutation is not the major reason for Wnt/β-catenin activation in breast cancer. Dishevelled-associated antagonist of β-catenin homolog 2 (DACT2) is a negative regulator of β-catenin and acts as a tumor suppressor in numerous cancer types; however, the expression change and potential role of DACT2 in breast cancer is unknown. The present study detected the expression and function of DACT2 in breast cancer progression. It was identified that the expression of DACT2 significantly decreased in breast cancer tissues compared with paired adjacent normal breast tissues. Additional investigation demonstrated that the hypermethylation of DACT2 gene promoter contributes to the loss of the gene in breast cancer. It was also demonstrated that DACT2 is a tumor suppressor in breast cancer and inhibits the proliferation and invasion of breast cancer cells by repressing the expression of β-catenin target genes associated with tumor growth and metastasis. The present study indicates that the loss of DACT2 may contribute to breast cancer progression and provides a promising therapeutic target for the treatment of breast cancer.

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“…In this study, we searched for methylated TSG candidates for digestive cancers through epigenomic (CpG methylome) study and expression profiling of a paired colon cancer cell line (HCT116 and HCT116-DKO with double knock-out of DNMT1 and DNMT3B 18, 19), and identified a candidate 16q24 TSG - Junctophilin-3 ( JPH3 ) as a methylated target. We systematically evaluated the inactivation of JPH3 by promoter CpG methylation in colorectal and gastric cancers, further explored its functions and mechanisms in the development of these cancers.…”

Section: Introductionmentioning

confidence: 99%

Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers

Kuang¹,

Li²,

Tang³

et al. 2017

Theranostics

Self Cite

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Junctophilin (JPH) proteins stabilize junctional membrane complexes between plasma membrane and endoplasmic reticulum, also implicated in some human diseases. JPH3 mutations are linked to Huntington's disease-like 2 syndrome. Through epigenomic study of a colon cancer cell line pair (HCT116 and DKO), we identified JPH3 as a methylated novel tumor suppressor gene (TSG) candidate at 16q24. We further studied its epigenetic alterations and functions in digestive tumorigenesis. JPH3 expression at the RNA level was found to be frequently silenced or reduced in colorectal and gastric cancers due to its promoter CpG methylation, which is associated with tumor progression and poor survival of digestive cancer patients. Ectopic expression of JPH3 inhibited tumor cell growth in vitro and in vivo. JPH3 expression upregulated the cytosolic Ca2+ levels, and unfolded protein response gene expression upon endoplasmic reticulum stress. JPH3 also induced calpain activation and subsequent mitochondrial membrane depolarization and cell apoptosis. Thus, JPH3 was identified as a novel TSG methylated in colorectal and gastric tumors which promotes mitochondrial-mediated apoptosis, also as a potential metastasis and survival biomarker for digestive cancers.

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Characterization of the Nasopharyngeal Carcinoma Methylome Identifies Aberrant Disruption of Key Signaling Pathways and Methylated Tumor Suppressor Genes

Abstract: The NPC methylome shows a special high-degree CpG methylation epigenotype, similar to the Epstein-Barr virus-infected gastric cancer, indicating a critical epigenetic etiology for NPC pathogenesis.

Cited by 51 publications

References 86 publications

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Methylation of DACT2 contributes to the progression of breast cancer through activating WNT signaling pathway

Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers

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