Tumor suppressor BLU inhibits proliferation of nasopharyngeal carcinoma cells by regulation of cell cycle, c-Jun N-terminal kinase and the cyclin D1 promoter

Zhang, Xiangning; Liu, Hui; Li, Binbin; Huang, Ping; Shao, Jian Yong; He, Zhiwei

doi:10.1186/1471-2407-12-267

Cited by 18 publications

(18 citation statements)

References 21 publications

(36 reference statements)

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“…The BLU protein is ~50 kDa and contains a MYND zinc finger DNA binding domain at its C-terminus, which was similar to the domains found in transcription repressors such as ETO (MTG8) and BS69 (10)(11)(12). As reported in previous studies, BLU served as a tumor suppressor in human nasopharyngeal carcinoma and ovarian carcinomas via inhibiting proliferation, inducing apoptosis and anti-angiogenic (13)(14)(15)(16). Moreover, BLU was found frequently inactivated by the promoter hypermethylation in various human cancers, which could be restored by demethylating agent 5-Aza treatment (17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 56%

Inactivation of BLU is associated with methylation of Sp1-binding site of BLU promoter in gastric cancer

Xiao¹,

Yu²,

Shi³

et al. 2015

International Journal of Oncology

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BLU is a candidate tumor suppressor gene, which is epigenetically inactivated in many human malignancies. However, the expression and biological functions of BLU in gastric cancer has not yet been reported. In the present study, we identified a functional BLU promoter which was regulated by the transcription activator Sp1. Bisulfite sequencing and qRT-PCR assays indicated that the silence of BLU expression in gastric cancer was significantly associated with DNA hypermethylation of BLU promoter including -39 CpG site located in the Sp1 transcription element. The expression of BLU was notably restored in AGS and SGC7901 cells following the demethylation-treatment with 5'-Aza-2'-deoxycytidine. Moreover, the results from ChIP, EMSA and luciferase reporter gene showed that -39 CpG methylation could prevent Sp1 from binding to the promoter of BLU and decreased transcription activity of the BLU gene by ~70%. In addition, knockdown of BLU significantly promoted cellular proliferation and colony formation in gastric cancer cells. In conclusion, we identified a novel functional BLU promoter and proved that BLU promoter activity was regulated by Sp1. Furthermore, we found that hypermethylated -39 CpG in BLU proximal promoter directly reduced its binding with Sp1, which may be one of the mechanisms accounting for the inactivation of BLU in gastric cancer.

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Section: Introductionmentioning

confidence: 56%

Inactivation of BLU is associated with methylation of Sp1-binding site of BLU promoter in gastric cancer

Xiao¹,

Yu²,

Shi³

et al. 2015

International Journal of Oncology

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“…In fact, the function of ZMYND10 protein, its encoded protein, has been reported as inhibitor of colony formation of cancer cells, and found it could be activated by environmental stresses such as heat sock and its regulated by E2F 13 . Moreover, tumor suppressor ZMYND10 inhibits proliferation of NPC cells by regulation of cell cycle, c-Jun N-terminal kinase and the cyclin D1 promoter 19 . Recently, growing evidences proved that the loss of ZMYND10 expression was downregulated correlated with promoter hypermethylation 12,13,19 .…”

Section: Discussionmentioning

confidence: 99%

Characteristic of ZMYND10 Gene�s Promoter Hypermethylation in Nasopharyngeal Carcinoma Biopsies from Vietnamese Patients

Lao

2019

Asian Journal of Pharmaceutical Research and Health Care

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Silencing of tumor suppressor gene, which caused by the DNA hypermethylation, an epigenetic modification, has been reported to be involved in human various cancers, including nasopharyngeal carcinoma. The aims of this study were to identify and evaluate the hypermethylation frequency of the ZMYND10 promoter, which located at 3p21.3, in nasopharyngeal biopsies from Vietnamese patients by Nested Methylation Specific PCR (Nested MSP). In current study, ninety tumor biopsies and ninety healthy samples, which were obtained from Cho Ray hospital, were enrolled into study. As the results, the hypermethylation frequency of ZMYND10 gene promoter was more frequent in tumor biopsies. In detail, the hypermethylation frequency of ZMYND10 gene promoter were 81.11% (73 of 90 samples), and 45.56% (41 of 90 samples) for in NPC biopsies and non-cancerous specimens. A trend toward positive association was found between hypermethylation of ZMYND10 gene and nasopharyngeal carcinoma (p < 0.0007). Additionally, the high Odds ratio (OR) and Relative risk were observed (OR = 5.13, RR = 2.49) (p <0.0001). In conclusion, our data suggested that the hypermethylation of ZMYND10 gene promoter is a significant in nasopharyngeal carcinoma in Vietnamese patients. NPC 4. Moreover, there is growing evidence demonstrating that the prevalent epigenetic changes, the hypermethylation of CpG islands in promoter regions of genes, the abnormalities at 3p21.3 region, contribute to many cell processes in cell-cycle regulation, apoptosis, signal transduction, cell adhesion, etc., which leading to the inactivation or less expression of these TSGs involves in many human tumorigenesis including NPC 5-7. Involvement of the 3p21.3 disorder, such as the hypermethylation of tumor suppressor gene, in various cancers including Nasopharyngeal Carcinoma (NPC) has been reported previously 8-11. Among several genes located at the 3p21.

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“…Functionally, BLU may suppress the tumor formation and progression via intracellular pathway targeting. Our previous study indicated that BLU downregulated the JNK pathway and inhibited the promoter activity of CCND1 , coding for cyclin D1, hence arresting the cell cycle in G1 phase [ 34 ]. Other studies have shown that BLU also downregulated proangiogenic cytokine to inhibit angiogenesis [ 41 ]; it also inactivated anti-apoptotic members of the Bcl-2 family to promote paclitaxel-induced apoptosis [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The tumor suppression of BLU has been indicated by its frequent loss in some human malignancies, but the underlying mechanisms are largely unknown. Previously, we have shown that similar to the tumor suppressors RASSF1A [ 32 ] and NGDR 2 [ 33 ], BLU down-regulates JNK signaling and inhibits the promoter activity of cyclin D1, thereby reducing its expression level to arrest the cell cycle in G1 phase [ 34 ]. The inhibition of cell cycle entry contributes to the proliferation inhibition of BLU .…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor BLU promotes TRAIL-induced apoptosis by downregulating NF-κB signaling in nasopharyngeal carcinoma

et al. 2016

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A putative tumor suppressor BLU mapped on the chromosomal 3p21 region, is frequently lost in human tumors including nasopharyngeal carcinoma (NPC). To explore the underlying mechanism of tumor suppression by BLU, its potential to promote apoptosis induced by TRAIL, an effector molecule elaborated by natural killer-T (NKT) cells was investigated. BLU was re-expressed in NPC-derived HNE1 cells by recombinant adenoviral infection and the cells were challenged with recombinant TRAIL. The growth inhibition of BLU was assayed and apoptosis was examined by flow cytometry-based tetramethylrhodamine ethyl ester (TMRE) and annexin V staining, cleavage of pro-caspase-8 and poly ADP ribose polymerase (PARP). The modulation of NF-κB pathway by BLU was evaluated by the reporter activity and estimation of the level of the molecules involved such as IKKalpha, p65 NF-κB, as well as NF-κB induced anti-apoptotic factors cFLIPL and cIAP2. The expression of BLU exerted in vitro and in vivo growth inhibitory effect and promoted TRAIL-induced apoptosis. This phenomenon was validated by FACS-based assays of mitochondrial membrane potential (BLU vs. Vector 87.8% ± 7.7% and 72.1%±6.7% at 6h exposure to TRAIL) and phosphatidylserine turnover (BLU vs. vector: 28.7%±2.9% and 22.6%±2.5%), as well as, enhanced caspapse-8 cleavage. Similar with the findings that BLU promotes chemotherapeutic agent-induced apoptosis, it also augmented death receptor-induced pathway through NF-κB pathway inhibition. In conclusion, BLU suppressed tumor formation by strengthening the antitumor immunity.

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Tumor suppressor BLU inhibits proliferation of nasopharyngeal carcinoma cells by regulation of cell cycle, c-Jun N-terminal kinase and the cyclin D1 promoter

Cited by 18 publications

References 21 publications

Inactivation of BLU is associated with methylation of Sp1-binding site of BLU promoter in gastric cancer

Inactivation of BLU is associated with methylation of Sp1-binding site of BLU promoter in gastric cancer

Characteristic of ZMYND10 Gene�s Promoter Hypermethylation in Nasopharyngeal Carcinoma Biopsies from Vietnamese Patients

Tumor suppressor BLU promotes TRAIL-induced apoptosis by downregulating NF-κB signaling in nasopharyngeal carcinoma

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