Dataset Information

ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer.

ABSTRACT: BACKGROUND:Recent studies suggested that ZMYND10 is a potential tumor suppressor gene in multiple tumor types. However, the mechanism by which ZMYND10 inhibits breast cancer remains unclear. Here, we investigated the role and mechanism of ZMYND10 in breast cancer inhibition. RESULTS:ZMYND10 was dramatically reduced in multiple breast cancer cell lines and tissues, which was associated with promoter hypermethylation. Ectopic expression of ZMYND10 in silenced breast cancer cells induced cell apoptosis while suppressed cell growth, cell migration and invasion in vitro, and xenograft tumor growth in vivo. Furthermore, molecular mechanism studies indicated that ZMYND10 enhances expression of miR145-5p, which suppresses the expression of NEDD9 protein through directly targeting the 3'-untranslated region of NEDD9 mRNA. CONCLUSIONS:Results from this study show that ZMYND10 suppresses breast cancer tumorigenicity by inhibiting the miR145-5p/NEDD9 signaling pathway. This novel discovered signaling pathway may be a valid target for small molecules that might help to develop new therapies to better inhibit the breast cancer metastasis.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6894283 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer.

Wang Yan Y Dan Liangying L Li Qianqian Q Li Lili L Zhong Lan L Shao Bianfei B Yu Fang F He Sanxiu S Tian Shaorong S He Jin J Xiao Qian Q Putti Thomas C TC He Xiaoqian X Feng Yixiao Y Lin Yong Y Xiang Tingxiu T

Clinical epigenetics 20191204 1

<h4>Background</h4>Recent studies suggested that ZMYND10 is a potential tumor suppressor gene in multiple tumor types. However, the mechanism by which ZMYND10 inhibits breast cancer remains unclear. Here, we investigated the role and mechanism of ZMYND10 in breast cancer inhibition.<h4>Results</h4>ZMYND10 was dramatically reduced in multiple breast cancer cell lines and tissues, which was associated with promoter hypermethylation. Ectopic expression of ZMYND10 in silenced breast cancer cells ind ...[more]

PMID: 31801619

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Project description:Gastric cancer is the second leading cause of cancer death and remains a major clinical challenge due to poor prognosis and limited treatment options. Therefore, the basic mechanisms underlying gastric tumorigenesis deserve investigation. Although regulation of the galactoside-binding lectin galectin-7 in cancer has been studied, its role in tumor formation and progression remains controversial. In this study, we investigated galectin-7 expression and its role in gastric cancer. Immunohistochemical staining using a tissue microarray of gastric cancer patients revealed significantly low expression levels of galectin-7 in malignant tissues compared with matched normal tissues, and decreased expression of galectin-7 in malignant tissues was associated with advanced TMN stage disease (p=0.034). Importantly, low expression of galectin-7 in normal tissues was associated with a poor survival rate (p=0.0561). Over-expression of galectin-7 in AGS gastric adenocarcinoma cells suppressed cell proliferation, migration, and invasion, whereas ablation of galectin-7 in KATO III gastric carcinoma cells reversed these properties. AGS cells that overexpressed galectin-7 could not form gastric tumors in xenografted mice. More than 70% hypermethylation was observed in 7 of 9 gastric cancer cell lines tested and 5-aza-cytidine treatment lowered galectin-7 expression by reducing methylation in 24 cancer cell lines from five different organ origins. We analyzed CpG islands in the galectin-7 genomic region and detected hypermethylation at +1566bp of exon 2, the predicted p53 binding region. DNA hypermethylation of this region was also detected in gastric cancer tissues from 20 patients. Taken together, our data indicate that galectin-7 has a tumor suppressive function, and that the gene is epigenetically modified by DNA methylation and significantly down-regulated in gastric cancer. Further study of galectin-7 regulation may lead to improved gastric cancer diagnosis and therapy.

Project description:BackgroundIn hepatocellular carcinoma (HCC), histone deacetylases (HDACs) are frequently overexpressed. This results in chromatin compaction and silencing of tumor-relevant genes and microRNAs. Modulation of microRNA expression is a potential treatment option for HCC. Therefore, we aimed to characterize the epigenetically regulated miR-129-5p regarding its functional effects and target genes to understand its relevance for HCC tumorigenesis.MethodsGlobal miRNA expression of HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B) and normal liver cell lines (THLE-2, THLE-3) was analyzed after HDAC inhibition by miRNA sequencing. An in vivo xenograft mouse model and in vitro assays were used to investigate tumor-relevant functional effects following miR-129-5p transfection of HCC cells. To validate hepatoma-derived growth factor (HDGF) as a direct target gene of miR-129-5p, luciferase reporter assays were performed. Survival data and HDGF expression were analyzed in public HCC datasets. After siRNA-mediated knockdown of HDGF, its cancer-related functions were examined.ResultsHDAC inhibition induced the expression of miR-129-5p. Transfection of miR-129-5p increased the apoptosis of HCC cells, decreased proliferation, migration and ERK signaling in vitro and inhibited tumor growth in vivo. Direct binding of miR-129-5p to the 3'UTR of HDGF via a noncanonical binding site was validated by luciferase reporter assays. HDGF knockdown reduced cell viability and migration and increased apoptosis in Wnt-inactive HCC cells. These in vitro results were in line with the analysis of public HCC datasets showing that HDGF overexpression correlated with a worse survival prognosis, primarily in Wnt-inactive HCCs.ConclusionsThis study provides detailed insights into the regulatory network of the tumor-suppressive, epigenetically regulated miR-129-5p in HCC. Our results reveal for the first time that the therapeutic application of mir-129-5p may have significant implications for the personalized treatment of patients with Wnt-inactive, advanced HCC by directly regulating HDGF. Therefore, miR-129-5p is a promising candidate for a microRNA replacement therapy to prevent HCC progression and tumor metastasis.

Dataset Information

ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer.

Publications

ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer.

Similar Datasets

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